KR20040045466A - Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease - Google Patents

Abstract

The present invention provides compounds of formula (I), wherein azabicyclo is formula (II-VII) and W is formula (VIII-X). The compound may be in the form of a pharmaceutical salt or composition, racemic mixture, or pure enantiomer thereof. Compounds of formula (I) are useful in pharmaceuticals known to include α7.

Description

AZABICYCLIC-SUBSTITUTED FUSED-HETEROARYL COMPOUNDS FOR THE TREATMENT OF DISEASE}

In general, cell surface receptors are good and identified drug targets. nAChR comprises a large family of ligand-gate ion channels that control neuronal activity and brain function. The receptor has a pentagonal structure. In mammals, the gene family consists of nine alpha and four beta subunits that co-associate to form multiple subtypes of receptors with specific pharmacology. While acetylcholine is an endogenous regulator of all subtypes, nicotine non-selectively activates all nAChRs.

α7 nAChR is one receptor system that has proven to be a difficult target to test. Routine native a7 nAChR cannot be stably expressed in most mammalian cell lines (Cooper and Millar, J. Neurochem., 1997, 68 (5): 2140-51). Another feature that enables the functional analysis of α7 nAChR attack is that the receptor is rapidly inactivated (100 milliseconds). This rapid deactivation greatly limits the functional analysis that can be used to measure channel activity.

Recently, Eisele et al. Described the pore-forming C-terminal domain of the N-terminal ligand binding domain of α7 nAChR [Eisele et al., Nature, 366 (6454), p 479-83, 1993] and the 5-HT ₃ receptor. It was pointed out that the chimeric receptor formed in between is well expressed in Xenopus oocytes with nicotinic agonist sensitivity. Ice et al. Used the N-terminus of the algae (chicken) form α7 nAChR receptor and the C-terminus of the mouse form 5-HT ₃ gene. However, under physiological conditions α7 nAChR is a calcium channel, while 5-HT ₃ R is a sodium and potassium channel. Indeed, Isle et al teach that chicken α7 nAChR / mouse 5-HT ₃ R does not conduct calcium but is in fact blocked by calcium ions, thus acting very differently from the native α7 nAChR with pore elements. WO 00/73431 A2 reports analytical conditions that allow 5-HT ₃ R to conduct calcium. The assay can be used to screen for agonist activity at the receptor.

US Pat. No. 6,054,464 describes the use of intermediates in intermediates and synthesis, as well as azabicyclic esters of carbamic acid, which are useful for therapies, especially the treatment or prevention of mental and intellectual impairment disorders.

U. S. Patent No. 5,977, 144 discloses compositions for benzylidene- and cinnamildene-anabasane and methods of using the compositions to treat conditions associated with defects or dysfunction of nicotinic subtype brain receptors. The compositions target α7 receptor subtypes with little or no activity of α4 β2 or other receptor subtypes.

US Pat. No. 5,599,937 discloses heteroaromatic quinuclidins used to treat diseases related to muscarinic receptor function.

US Pat. No. 5,561,149 discloses a medicament suitable for the treatment of stress-related psychiatric disorders, increased arousal, treatment of rhinitis or serotonin-induced disorders, and / or in combination with other active agents that increase its bioavailability, or nasal administration. Disclosed is the use of mono or bicyclic carbocyclic, or heterocyclic carboxylic acids, esters or amides or imidazolyl carbazoles in the preparation thereof.

U.S. Patent 5,543,426 discloses the use of certain 3,7-disubstituted indole compounds for treating depression or cognitive disorders.

US Pat. No. 5,434,161 discloses imidazopyridine as a serotonergic 5-HT ₃ antagonist.

U.S. Patent 5,362,740 discloses dihydrobenzofuran carboxamides useful for treating CNS disorders in mammals, but movement disorders and / or vomiting and / or pain and / or migraine headaches.

U.S. Patent No. 5,352,685 discloses stomach aches and pains such as heartburn, abdominal bloating, anorexia, epigastric discomfort, abdominal pain, nausea, vomiting, etc. caused by underlying diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastritis, and gastrointestinal sputum. Disclosed are thieno [3,2-b] pyridine derivatives that are effective in the prophylaxis and treatment regimens of symptoms caused by impaired exercise.

US Pat. No. 5,342,845 discloses indole derivatives and drugs. The compounds of the invention are disclosed to be effective as gastrointestinal motility modulators, anti-migraine, antipsychotic or anti-anxiety drugs and for dementia or orthostatic hypotension.

U.S. Patent 5,322,951 discloses certain 1- (2,3-dihydro- useful for preparing 1- (2,3-dihydro) -1-carboxamide end products with 5-HT M-receptor antagonist activity. Indole) carbonyl intermediates are disclosed.

US Pat. No. 5,272,154 discloses 3,7 substituted indole and indazole compounds and pharmaceutical compositions containing them, which are disclosed to be useful in the treatment of psychiatric disorders.

U. S. Patent No. 5,217, 975 discloses azabicyclic compounds for treating dementia.

US Pat. No. 5,039,680 discloses 5-HT ₃ antagonists which interfere with or reduce dependence on dependency-inducing agents.

U.S. Patent 5,001,133 discloses benzoic acid heterocyclic amides and esters substituted as serotonin M antagonists.

U.S. Pat. No. 4,985,437 describes the use of certain compounds that act as 5-hydroxytryptamine (5-HT) antagonists at the 5-HT ₃ receptor for treating cognitive disorders such as attention and memory deficits and dementia conditions. It starts.

U.S. Patent 4,983,600 discloses heterocyclic compounds useful as 5-HT ₃ antagonists.

US Pat. No. 4,973,594 discloses the use of compounds that act as 5-hydroxytryptamine (5-HT) antagonists at the 5-HT ₃ receptor for treating depression.

US Pat. No. 4,937,247 discloses 1-acyl indazole disclosed to have 5-HT ₃ antagonist activity.

US Pat. No. 4,935,511 discloses benzoxazine and benzoxazepine carboxamide 5-HT ₃ antagonist properties, including CNS, anti-vomit and gastric motility activity, with no significant D ₂ receptor binding affinity.

US Pat. No. 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid useful as an intermediate for 5-HT ₃ antagonists.

US Pat. No. 4,920,219 discloses substituted saturated and unsaturated indole quinolines and benzazine carboxamides and their useful uses as 5-HT ₃ antagonists with no significant D ₂ receptor binding properties and CNS and gastric motility activity. do.

US Pat. No. 4,920,127 discloses its use as substituted indole and 5-HT ₃ receptor antagonists.

US Pat. No. 4,910,193 discloses the treatment of gastrointestinal disorders.

US Pat. No. 4,888,353 discloses carboxamides useful as antiemetic or antipsychotic agents.

US Patent 4,882,327 discloses certain heterocyclic N-substituted carboxamides having 5-HT ₃ receptor antagonist activity.

US Pat. No. 4,845,092 discloses methods of treating visceral pain in mammals, including humans.

US Pat. No. 4,835,162 discloses agonists and antagonists for nicotine as smoking inhibitors.

U.S. Patent 4,822,795 discloses pharmaceutically useful esters and amides.

US Pat. No. 4,803,199 discloses heterocyclic acid esters and amide or alkylene bridged piperidines which are pharmaceutically useful as serotonin M antagonists.

US Pat. No. 4,798,829 discloses 1-azabicyclo [3.2.2] nonane derivatives having gastric motility enhancing activity and / or anti-vomiting activity and / or 5-HT receptor antagonist activity.

US Pat. No. 4,797,406 discloses amides and esters containing bridged piperidine and use as serotonin M antagonists.

US Pat. No. 4,721,720 discloses methods of treating vomiting, anxiety and / or irritable bowel syndrome.

U.S. Patent 4,612,319 discloses bridged quinolizinidinylamides, compositions containing them and methods of use thereof.

US Pat. No. 4,605,652 discloses a method for improving memory or correcting memory deficiencies with arylamido (and arylthioamido) -azabicycloalkanes, and pharmaceutically acceptable acid addition salts, hydrates and alcoholates thereof. .

WO 01/60821 A1 discloses novel biarylcarboxamides and their use in therapies, in particular in the prophylactic treatment of mental and intellectual impairment conditions.

WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives and their use in therapies, especially in the prophylactic treatment of mental and intellectual impairment disorders.

WO 00/73431 A2 discloses two binding assays that directly measure the affinity and selectivity of a compound at α7 nAChR and 5-HT ₃ R. Combination applications of these functions and binding assays can be used to identify compounds that are selective agonists of α7 nAChR.

WO 99/20633 discloses benzoazine derivatives having antagonist activity on the 5-HT ₃ / 5-HT ₄ receptor.

WO 97/35860 discloses novel benzimidazole derivatives having affinity for serotonergic 5-HT ₃ / 5-HT ₄ receptors.

WO 96/33186 discloses dihydrobenzofuran derivatives substituted as 5-HT ₄ agonists.

WO 95/27490 discloses serotonin antagonists (5-HT ₃ ) for treating fibromyalgia.

WO 95/04742 discloses trophyl 7-azaindol-3-ylcarboxyamide as an antitussive agent.

WO 92/10494 discloses novel compounds that are 5-HT ₃ receptor antagonists.

WO 91/17161 discloses isoquinoline amides and esters as 5-HT ₃ receptor antagonists.

WO 91/09593 discloses 5-HT ₃ antagonists for treating myocardial instability associated with nausea, bradycardia or hypotension.

WO 90/14347 A discloses N-quinuclidinyl-indolecarboxamide derivatives as antiemetic agents, as summarized in chemical abstract 1991: 143, 158.

EP 512 350 A2 provides 3- (indolyl) useful for the treatment of diseases characterized by excessive or increased sensitivity to serotonin, such as psychosis, nausea, vomiting, dementia or other cognitive diseases, migraine, and diabetes. -2-carboxamido) quinuclidin is disclosed. The compound can be used to control anxiety, aggressiveness, depression and pain. The compound is disclosed as a serotonin 5-HT ₃ antagonist.

EP 496 064 A1 discloses a process for the preparation of substituted benzofuran derivatives. The compound is disclosed to be a useful 5-HT ₃ receptor antagonist.

EP 483 836 A1 discloses pyrazolo [1,5-a] pyridine-3-carboxylic acid derivatives, methods for their preparation and serotonin receptor antagonists containing them as active ingredients.

DE 3810552 A1 is an indolyl-, benzo [b] thiophenyl-, benzo [b] furancarboxylic acid or 4-amino-2-methoxy-benzoic acid with N-heterocyclic or N-heterobicyclic alcohol or amine Esters and amides are disclosed. The disclosed compounds are anti-arrhythmic for gastrointestinal disorders, gastric disorders, gastritis ulcers, gallbladder, convulsive colon, Crohn's disease, ulcerative colitis, carcinoid syndrome, various types of diarrhea, and in particular against pain, especially migraines. Have activity. The compound also speeds up gastric emptying and controls gastroduodenal and gastroesophageal reflux, disorders of esophageal motility, hiatus hernia, cardiac insufficiency, hypopotonic stomach, paralytic ileus, manic psychosis and other psychosis It is disclosed as. The compounds are also disclosed to be useful for improving the nasal absorption of other agents in the treatment of stress related diseases, senility and for example vomiting.

Bioorg. & Med. Chem. Lett. 11 (2001) 319-321, 5-HT ₃ antagonist trophysetron (ICS 205-930) is discussed as an effective and selective α7 nicotinic receptor partial agonist.

In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that brain α7 nicotinic receptors may be an important therapeutic target for treating Alzheimer's disease using DMXBA, known as GTS-21.

Bioorg. & Med. Chem. Lett. 9 (1999) 1895-1900, the discovery of highly potent, function-selective muscarinic M1 agonists is discussed.

Bioorg. & Med. Chem. Lett. 4 (1994) 695-698, pyrazolo [1,5-a] pyridine and pyrazolo [1,5-b] pyridazine are discussed as 5-HT ₃ antagonists.

Eur. J. Med. Chem., 34 (1999) 415-422, benzimidazole-2-carboxylic acid amides and esters are discussed as a novel structural class of 5-HT ₃ ligands.

Summary of the Invention

The present invention discloses a compound of formula (I) or a pharmaceutical composition, a pharmaceutically acceptable salt, a racemic mixture, or pure enantiomers thereof:

Wherein azabicyclo is

ego,

W is

This,

Provided that the bond between the —C (═X) —group and the W group can be attached to any available carbon atom in the W group as shown in R ₃ , R ₆ and R ₁₅ ;

X is O or S;

R ₀ is H, lower alkyl, substituted lower alkyl or halogenated lower alkyl;

Each R ₁ is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl or substituted naphthyl;

Each R ₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, aryl, F, Cl, Br, I or R ₂ is absent when k ₂ , k ₅ or k ₆ is 0;

R _2-3 is H, alkyl, substituted alkyl, halogenated alkyl, F, Cl, Br or I;

k ₂ is 0 or 1;

k ₅ and k ₆ are independently 0, 1 or 2;

A --- A '--- A "is N (R ₄ ) -C (R ₃ ) = C (R ₃ ), N = C (R ₃ ) -C (R ₁₅ ) ₂ , C (R ₃ ) = C (R ₃ ) -N (R ₄ ), C (R ₃ ) ₂ -N (R ₄ ) -C (R ₃ ) ₂ , C (R ₁₅ ) ₂ -C (R ₃ ) = N, N ( R ₄ ) -C (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -C (R ₃ ) ₂ -N (R ₄ ), OC (R ₃ ) = C (R ₃ ), OC (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -OC (R ₃ ) ₂ , C (R ₃ ) = C (R ₃ ) -O, C (R ₃ ) ₂ -C (R ₃ ) ₂ -O, SC (R ₃ ) = C (R ₃ ), SC (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -SC (R ₃ ) ₂ , C ( R ₃ ) = C (R ₃ ) -S or C (R ₃ ) ₂ -C (R ₃ ) ₂ -S;

Each R ₃ is independently a bond with the core molecule, provided that only R ₃ is the bond and R ₆ or R ₁₅ is not such a bond, H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted Alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, -CN, -N0 ₂ , F, Br, Cl, I, -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -S (O) ₂ R ₁₉ , -C (O) R ₁₉ , -CO ₂ R ₁₉ , aryl, R ₇ or R ₉ ;

J, L, M and Q are N or C (R ₆ ), provided that only one of J, L, M or Q is N and the rest are C (R ₆ ), and further that the core molecule is a When attached to the denyl moiety Q is C (H) and additionally there is only one attachment to the core molecule;

G and Y are C (R ₆ ), provided that when the molecule is attached to the phenyl moiety in Y, G is CH;

R ₄ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R ₇ or R ₉ ;

Each R ₅ is independently H, lower alkyl or lower alkenyl;

Each R ₆ is independently H, F, Br, I, Cl, -CN, -CF ₃ , -OR ₅ , -SR ₅ , -N (R ₅ ) ₂ or a bond to a core molecule, provided that only R ₆ Only one is said bond and R ₃ or R ₁₅ is not said bond);

V is selected from O, S or N (R ₄ );

R ₇ contains 1 to 3 heteroatoms independently selected from the group consisting of = N—, —N (R ₁₇ ) —, —O— and —S— in the ring, 0 to 1 substituents selected from R ₁₈ Is a 5-membered heteroaromatic mono-cyclic moiety having 0 to 3 substituents independently selected from F, Cl, Br or I, or R ₇ is a 5-membered ring having the formula A 9-membered fused ring moiety having a fused 6-membered ring:

Wherein, G ₁ is O, S or NR ₁₇ ,

Wherein G is C (R ₁₆ ) or N, each G ₂ and G ₃ is independently selected from C (R ₁₆ ) ₂ , C (R ₁₆ ), O, S, N and N (R ₁₈ ) Provided that G ₂ and G ₃ are both O at the same time, S at the same time, or not O and S at the same time,

Wherein G is C (R ₁₆ ) or N, and each G ₂ and G ₃ are independently selected from C (R ₁₆ ) ₂ , C (R ₁₆ ), O, S, N and N (R ₁₇ ) , Each 9-membered fused ring moiety bears 0 to 1 substituents selected from R ₁₈ and further carries 0 to 3 substituent (s) independently selected from F, Cl, Br or I, wherein R _{The 7} moiety is attached to another substituent as defined in Formula (I) as valency is allowed at any position on any ring;

Each R ₈ is independently H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R ₇ , R ₉ , Phenyl or substituted phenyl;

R ₉ contains 1 to 3 heteroatoms selected from = N- in the ring and 0 to 1 substituents selected from R ₁₈ and 0 to 3 substituent (s) independently selected from F, Cl, Br or I Or a ₉ -membered heteroaromatic mono-cyclic moiety having 1 to 3 heteros selected from = N-, including but not limited to, quinolinyl or isoquinolinyl in one or all two rings A 10-membered heteroaromatic acyclic portion containing an atom, wherein each 10-membered fused ring portion is 0 to 1 substituents selected from R ₁₈ and 0 independently selected from F, Cl, Br or I Has from 3 to 3 substituent (s) and, where valences are acceptable, a bond attached directly or indirectly to the core molecule;

Each R ₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl, 1 substituent selected from a cycloalkyl, R ₁₃ is substituted by 1 substituent selected from alkyl, R ₁₃ is substituted by 1 substituent selected from R ₁₃ Substituted heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl or substituted phenyl;

Each R ₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl or halogenated heterocycloalkyl;

R ₁₂ is —N0 ₂ , —CN, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ or- NR ₁₁ S (O) ₂ R ₁₁ ;

R ₁₃ is -CN, -CF ₃ , -N0 ₂ , -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ or -NR ₁₁ S (O) ₂ R ₁₁ ;

Each R ₁₄ is H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, -CN, -NO ₂ , -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -S (O) ₂ R ₁₉ , -C (O) R ₁₉ ,- CO ₂ R ₁₉ , aryl, R ₇ or R ₉ ;

Each R ₁₅ is independently alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, -CN, -N0 ₂ , -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -CO ₂ R ₁₉ , aryl, R ₇ , R ₉ or to the core molecule Only one R ₁₅ is said bond and R ₆ or R ₃ is not said bond;

Each R ₁₆ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, F, Cl, Br, I, -N0 ₂ , -CN, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ , -NR ₁₁ S (0) ₂ R ₁₁ or a bond attached directly or indirectly to a core molecule, provided that the bond to the core molecule in the 9-membered fused ring moiety is Only one, in addition, the fused ring moiety is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -NO ₂ , -C (O) NR ₁₁ R ₁₁ , -CN, -NR ₁₁ C (O) R ₁₁ , -S (O ) 0 to 1 selected from ₂ NR ₁₁ R ₁₁ or -NR ₁₁ S (O) ₂ R ₁₁ Bearing substituents, further, the fused ring moiety bears 0 to 3 substituent (s) selected from F, Cl, Br or I;

R ₁₇ has 1 substituent selected from H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, -SO ₂ R ₈ or R _{18 and} is selected from F, Cl, Br or Phenyl further having 0 to 3 substituents independently selected from I;

R ₁₈ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O ) NR ₁₁ R ₁₁ , -CN, -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ , -NR ₁₁ S (O) ₂ R ₁₁ , -NO ₂ , F, Cl, Br , Alkyl substituted with 1 to 4 substituent (s) independently selected from I or R ₁₃ , F, Cl, Br, cycloalkyl substituted with 1 to 4 substituent (s) independently selected from I or R ₁₃ , or Heterocycloalkyl substituted with 1 to 4 substituent (s) independently selected from F, Cl, Br, I or R ₁₃ ;

R ₁₉ is H, alkyl, cycloalkyl, substituted alkyl, halogenated alkyl, substituted phenyl or substituted naphthyl.

Compounds of formula (I) are used to treat a disease or condition wherein the disease, disorder and / or condition is any one or more of the following diseases or a combination of the following diseases: symptoms of cognitive and attention deficits in Alzheimer's disease, Alzheimer's disease Neurodegeneration associated with diseases such as illness, elderly dementia (mild cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, general anxiety disorder, post-traumatic stress disorder, mood and Emotional disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with common and brain tumors, AIDS dementia complex, dementia associated with Down syndrome, dementia associated with Lewy body, Huntington's disease, Parkinson's disease, Difficulty controlling food intake, including delayed dyskinesia, Pick's disease, bulemia and anorexia nervosa, smoking cessation Withdrawal, Gilles de la Tourette's syndrome (Gilles de la Tourette's Syndrome), age-related dependency drug discontinuation-related macular degeneration, the symptoms associated with glaucoma, neurodegeneration associated with glaucoma, or pain.

Embodiments of the invention may include one or more of the following compounds or combinations of the following compounds.

A compound of formula I, wherein X is O.

A compound of formula I, wherein X is S.

A compound of formula I wherein the azabicyclo is any one or more of I, II, III, IV, V or VI.

A compound of formula I, wherein W is at least one of (a), (b) or (c).

A compound of formula I, wherein W is at least one of the following compounds: thieno [2,3-b] pyridin-2-yl, thieno [2,3-b] pyridin-5-yl, thieno [2,3 -b] pyridin-6-yl, thieno [3,2-b] pyridin-2-yl, thieno [3,2-b] pyridin-5-yl, thieno [3,2-b] pyridine- 6-yl, thieno [2,3-c] pyridin-2-yl, thieno [2,3-c] pyridin-5-yl, thieno [3,2-c] pyridin-2-yl, thi No [3,2-c] pyridin-6-yl, furo [3,2-c] pyridin-2-yl, furo [3,2-c] pyridin-6-yl, furo [2,3-b] Pyridin-2-yl, furo [2,3-c] pyridin-2-yl, furo [2,3-c] pyridin-5-yl, 2,3-dihydrofuro [2,3-c] pyridine- 5-yl, 1H-pyrrolo [2,3-c] pyridin-5-yl, thieno [3,4-c] pyridin-6-yl, benzothieno [3,2-c] pyridine-3- One, benzothieno [2,3-c] pyridin-3-yl, benzofuro [3,2-c] pyridin-3-yl or benzofuro [2,3-c] pyridin-3-yl,

Any of the above compounds may be selected from F, Br, Cl, I, -CN, -NO ₂ , -CF ₃ , on up to 4 different carbon atoms, as valency permits and as permitted by the definition of W; -OR ₅ , -OR ₁₉ , -SR ₅ , -SR ₁₉ , -N (R ₅ ) ₂ , -N (R ₁₀ ) ₂ , -C (O) R ₁₉ , -CO ₂ R ₁₉ , -C (O ) N (R ₁₀ ) ₂ , -S (O) ₂ R ₁₉ , alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, Optionally substituted with aryl, R ₇ , R ₉ ,

In addition, any of the above compounds may be alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl on nitrogen as permitted by the definition of W. , Optionally substituted with substituted heterocycloalkyl, R ₇ or R ₉ ,

However, one carbon is used to bond W to the core molecule. Those skilled in the art will recognize which substitutions are allowed by comparing the parts named for W with the allowed parts.

As allowed by the definition of W, (a), (b) or (c) is F, Br, Cl, I, -CN, -CF ₃ , -OR ₅ , -SR ₅ , -N (R ₅ ) ₂ , -C (O) R ₅ , -CO ₂ R ₅ , -C (O) N (R ₁₀ ) ₂ , -S (O) ₂ R ₅ , lower alkyl, lower substituted alkyl or lower alkynyl A compound of formula (I), optionally substituted with up to 4 substituents,

Wherein R ₁₀ is H, lower halogenated alkyl or -CN, -CF ₃ , -NO ₂ , -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (0) R ₁₁ , -S (0) ₂ NR ₁₁ R ₁₁ or lower alkyl optionally substituted with -NR ₁₁ S (0) ₂ R ₁₁ , wherein R ₁₁ is H, Lower alkyl, lower halogenated alkyl, lower substituted alkyl. Since those skilled in the art are within the group R ₅ is the group of the sub-group in R _19, -OR _5, in the case of _{-OR 19, -SR 19, -C (} O) R 19 or -CO ₂ R ₁₉ substituent is acceptable - It will be appreciated that SR ₅ , -C (O) R ₅ or -C0 ₂ R ₅ are also allowed. One skilled in the art can also ascertain which substituents are allowed on carbon or nitrogen as permitted by the definition of W.

Lower alkynyl is a straight and branched chain moiety having 2 to 4 carbon atoms and at least one carbon-carbon triple bond.

Another group of compounds of Formula I include compounds wherein R ₁ is H, alkyl or cycloalkyl.

Another group of compounds of Formula I include compounds wherein the azabicyclo is II, V or VI, wherein each k ₂ , k ₅ and k ₆ are independently 0 or 1. Another group of compounds of formula I include those compounds R ₂ is alkyl, halogenated alkyl, or substituted alkyl, k _2, k _5, or k ₆ is 0 if R ₂ is not present. Another group of compounds of Formula I include compounds wherein R ₂ is absent when R ₁ is H or lower alkyl and R ₂ is lower alkyl or k ₂ , k ₅ or k ₆ is zero.

Another group of compounds of Formula I include compounds wherein azabicyclo is I and R ₂ is alkyl, halogenated alkyl or substituted alkyl, or azabicyclo is III or IV and R _2-3 is H, alkyl or substituted alkyl .

A compound of formula (I) which is any free compound or combination of

Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide;

Exo-4 (R) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide;

Exo-N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide;

(+)-N- [endo-1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-5-carboxamide;

(-)-N- [endo-1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N-[(exo) -azabicyclo [2.2.1] hept-3-yl] furo [3,2-c] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carr Boxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide;

Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide;

(Exo) -N- [1-azabicyclo [3.2.1] oct-3-yl] -3-methylfuro [2,3-c] pyridine-5-carboxamide;

(3R, 5R) -N- [1-azabicyclo [3.2.1] oct-3-yl] -3-methylfuro [2,3-c] pyridine-5-carboxamide;

Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -furo [2,3-b] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -furo [2,3-b] pyridine-2-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -furo [2,3-b] pyridine-2-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -furo [2,3-b] pyridine-2-carboxamide;

Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-2-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-b] pyridine-2-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-2-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-b] pyridine-5-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-6-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-2-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-c] pyridine-2-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-c] pyridine-2-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-2-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-2-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-2-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-6-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide;

Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-c] pyridine-5-carboxamide;

Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-c] pyridine-6-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (1-azabicyclo [2.2.1] hept-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide;

N- [exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl] -3-chlorofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; or

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide.

With respect to all the compounds identified, the naming of specific enantiomers is not intended to limit the scope of the present invention, but is intended to illustrate. Specific naming of enantiomers includes racemic mixtures of these compounds. For example, the nomenclature of exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide is defined herein. Exo- (rac) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide in the range. Where pure enantiomers are discussed, the compounds are racemic mixtures or pure enantiomers thereof. If the azabicyclo is II, the pure enantiomers include exo-4 (S) 1-azabicyclo [2.2.1] hept-3-yl. If the azabicyclo is V, the pure enantiomers include exo-3 (R), 5 (R) 1-azabicyclo [3.2.1] oct-3-yl.

A compound of formula (I) which is any free compound or combination of

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-vinylfuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-ethynylfuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3-hydroxyprop-1-ynyl) furo [3,2-c] pyridine- 6-carboxamide;

Methyl 3- (6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [3,2-c] pyridin-2-yl) prop 2-inoate;

2- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [3,2-c ] Pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-cyanofuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-chlorofuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-fluorofuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-iodofuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylthio) furo [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylamino) furo [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (formylamino) furo [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- [formyl (methyl) amino] furo [3,2-c] pyridine-6-carbox amides;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-[(trifluoroacetyl) amino] furo [3,2-c] pyridine-6-carbox Boxamide;

N-6- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-formylfuro [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (trifluoroacetyl) furo [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylsulfonyl) furo [3,2-c] pyridine-6-carboxamide;

Methyl 6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [3,2-c] pyridine-2-carboxylate;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-vinylthieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-ethynylthieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-prop-1-ynylthieno [3,2-c] pyridine-6-carboxamide ;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3-hydroxyprop-1-ynyl) thieno [3,2-c] pyridine -6-carboxamide;

Methyl 3- (6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [3,2-c] pyridin-2-yl) prop P-2-inoate;

2- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [3,2- c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-cyanothieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-chlorothieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-fluorothieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-iodothieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-trifluoromethylthieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylthio) thieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylamino) thieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (formylamino) thieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- [formyl (methyl) amino] thieno [3,2-c] pyridine-6-carbox Boxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-[(trifluoroacetyl) amino] thieno [3,2-c] pyridine-6- Carboxamides;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (cyclopropylamino) thieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- [dimethylamino] thieno [3,2-c] pyridine-6-carboxamide;

N-6- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [3,2-c] pyridine-2,6-dicarboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-formylthieno [3,2-c] pyridine-6-carboxamide;

2-acetyl-N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [3,2-c] pyridine-6-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (trifluoroacetyl) thieno [3,2-c] pyridine-6-carboxamide ;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylsulfonyl) thieno [3,2-c] pyridine-6-carboxamide;

Methyl 6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [3,2-c] pyridine-2-carboxylate;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-vinylfuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-ethynylfuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3-hydroxyprop-1-ynyl) furo [2,3-c] pyridine- 5-carboxamide;

Methyl 3- (5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [2,3-c] pyridin-3-yl) prop 2-inoate;

3- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c ] Pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-cyanofuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-fluorofuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-iodofuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylthio) furo [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylamino) furo [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (formylamino) furo [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [formyl (methyl) amino] furo [2,3-c] pyridine-5-carbox amides;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-[(trifluoroacetyl) amino] furo [2,3-c] pyridine-5-car Boxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (cyclopropylamino) furo [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide;

N-5- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-formylfuro [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (trifluoroacetyl) furo [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylsulfonyl) furo [2,3-c] pyridine-5-carboxamide;

Methyl 5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [2,3-c] pyridine-3-carboxylate;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-vinylthieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-ethynylthieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-prop-1-ynylthieno [2,3-c] pyridine-5-carboxamide ;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3-hydroxyprop-1-ynyl) thieno [2,3-c] pyridine -5-carboxamide;

Methyl 3- (5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [2,3-c] pyridin-3-yl) prop P-2-inoate;

3- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [2,3- c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-cyanothieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-chlorothieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-fluorothieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-iodothieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-trifluoromethylthieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylthio) thieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylamino) thieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (formylamino) thieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [formyl (methyl) amino] thieno [2,3-c] pyridine-5-car Boxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-[(trifluoroacetyl) amino] thieno [2,3-c] pyridine-5- Carboxamides;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (cyclopropylamino) thieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [dimethylamino] thieno [2,3-c] pyridine-5-carboxamide;

N-5- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [2,3-c] pyridine-3,5-dicarboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-formylthieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (trifluoroacetyl) thieno [2,3-c] pyridine-5-carboxamide ;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylsulfonyl) thieno [2,3-c] pyridine-5-carboxamide;

Methyl 5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [2,3-c] pyridine-3-carboxylate;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (phenylethynyl) furo [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3,3-trifluoroprop-1-ynyl) furo [2,3- c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3-difluoroprop-1-ynyl) furo [2,3-c] Pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (phenylethynyl) thieno [2,3-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3,3-trifluoroprop-1-ynyl) thieno [2,3 -c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3-difluoroprop-1-ynyl) thieno [2,3-c ] Pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (phenylethynyl) thieno [3,2-c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3,3,3-trifluoroprop-1-ynyl) thieno [3,2 -c] pyridine-5-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3,3-difluoroprop-1-ynyl) thieno [3,2-c ] Pyridine-5-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -2-methyl-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-methyl-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -2-ethyl-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -3-ethyl-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -4-methyl-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methylthio-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methoxy-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-chloro-furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-vinylfuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-ethynylfuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-cyanofuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethynylfuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-cyanofuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-fluorofuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-chlorofuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-bromofuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-iodofuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-mercaptofuro [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylthio) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylamino) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (formylamino) furo [3,2-c] pyridine-6-carboxamide;

2- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide;

2- (acetyl) methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(trifluoroacetyl) amino] furo [3,2-c] pyridine-6-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (benzoylamino) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diethylamino) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diisopropylamino) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-yl) furo [3,2-c] pyridine-6-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-yl) furo [3,2-c] pyridine-6-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-yl) furo [3,2-c] pyridine-6-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-yl) furo [3,2-c] pyridine-6-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (4-methylpiperazin-1-yl) furo [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (cyclopropylamino) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-ylcarbonyl) furo [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-ylcarbonyl) furo [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(4-methylpiperazin-1-yl) carbonyl] furo [3,2-c] Pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-ylcarbonyl) furo [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (aziridin-1-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (azetidin-1-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-formylfuro [3,2-c] pyridine-6-carboxamide;

2-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (trifluoroacetyl) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(phenyl) sulfonyl] furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylsulfonyl) furo [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -4-methyl-thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methylthio-thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methoxy-thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-chloro-thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-vinylthieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-ethynylthieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-prop-1-ynylthieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-cyanothieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-fluorothieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-chlorothieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-bromothieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-iodothieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-trifluoromethylthieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-mercaptothieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylthio) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylamino) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (formylamino) thieno [3,2-c] pyridine-6-carboxamide;

2- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,2-c] pyridine-6-carboxamide;

2- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,2-c] pyridine-6-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(trifluoroacetyl) amino] thieno [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (benzoylamino) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diethylamino) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diisopropylamino) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-yl) thieno [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-yl) thieno [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-yl) thieno [3,2-c] pyridine-6-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-yl) thieno [3,2-c] pyridine-6-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-yl) thieno [3,2-c] pyridine-6-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-6 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (cyclopropylamino) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- [dimethylamino] thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-ylcarbonyl) thieno [3,2-c] pyridine-6 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-ylcarbonyl) thieno [3,2-c] pyridine-6 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(4-methylpiperazin-1-yl) carbonyl] thieno [3,2-c ] Pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-ylcarbonyl) thieno [3,2-c] pyridine-6 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (aziridin-1-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (azetidin-1-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-formylthieno [3,2-c] pyridine-6-carboxamide;

2-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (trifluoroacetyl) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(phenyl) sulfonyl] thieno [3,2-c] pyridine-6-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylsulfonyl) thieno [3,2-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-vinylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -7-methyl-furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -7-methoxy-furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethynylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-cyanofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-fluorofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-iodofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-mercaptofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylthio) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (formylamino) furo [2,3-c] pyridine-5-carboxamide;

3- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

3- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(trifluoroacetyl) amino] furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (benzoylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diethylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diisopropylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-yl) furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-yl) furo [2,3-c] pyridine-5-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-yl) furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-yl) furo [2,3-c] pyridine-5-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (cyclopropylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-ylcarbonyl) furo [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(4-methylpiperazin-1-yl) carbonyl] furo [2,3-c] Pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (aziridin-1-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (azetidin-1-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-formylfuro [2,3-c] pyridine-5-carboxamide;

3-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (trifluoroacetyl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(phenyl) sulfonyl] furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylsulfonyl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -2-ethyl-furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-ethynylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-cyanofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-fluorofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-chlorofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-bromofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-iodofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-mercaptofuro [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylthio) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (formylamino) furo [2,3-c] pyridine-5-carboxamide;

2- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

2- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(trifluoroacetyl) amino] furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (benzoylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diethylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diisopropylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-yl) furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-yl) furo [2,3-c] pyridine-5-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-yl) furo [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-yl) furo [2,3-c] pyridine-5-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (cyclopropylamino) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-ylcarbonyl) furo [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(4-methylpiperazin-1-yl) carbonyl] furo [2,3-c] Pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (aziridin-1-ylcarbonyl) furo [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (azetidin-1-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-formylfuro [2,3-c] pyridine-5-carboxamide;

2-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (trifluoroacetyl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(phenyl) sulfonyl] furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylsulfonyl) furo [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -7-methyl-thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-methylthio-thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-methoxy-thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-chloro-thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-vinylthieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethynylthieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-prop-1-ynylthieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-cyanothieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-fluorothieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-chlorothieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-bromothieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-iodothieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-trifluoromethylthieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-mercaptothieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylthio) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylamino) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (formylamino) thieno [2,3-c] pyridine-5-carboxamide;

3- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-c] pyridine-5-carboxamide;

3- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-c] pyridine-5-carboxamide ;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(trifluoroacetyl) amino] thieno [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (benzoylamino) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diethylamino) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diisopropylamino) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-yl) thieno [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-yl) thieno [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-yl) thieno [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-yl) thieno [2,3-c] pyridine-5-car Boxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-yl) thieno [2,3-c] pyridine-5-carbox amides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (4-methylpiperazin-1-yl) thieno [2,3-c] pyridin-5 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (cyclopropylamino) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- [dimethylamino] thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-ylcarbonyl) thieno [2,3-c] pyridine-5 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-ylcarbonyl) thieno [2,3-c] pyridine-5 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(4-methylpiperazin-1-yl) carbonyl] thieno [2,3-c ] Pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-ylcarbonyl) thieno [2,3-c] pyridine-5 Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (aziridin-1-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (azetidin-1-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-formylthieno [2,3-c] pyridine-5-carboxamide;

3-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (trifluoroacetyl) thieno [2,3-c] pyridine-5-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(phenyl) sulfonyl] thieno [2,3-c] pyridine-5-carboxamide ; or

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylsulfonyl) thieno [2,3-c] pyridine-5-carboxamide.

A compound of formula (I) which is any free compound or combination of

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (l- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-car Boxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -furo [2,3-b] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -furo [2,3-b] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -furo [2,3-b] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-c] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-c] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-c] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-c] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-c] pyridine-2-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; or

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide.

A compound of formula (I) which is any free compound or combination of

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-ethynylfuro [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-cyanofuro [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-fluorofuro [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-chlorofuro [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-bromofuro [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-iodofuro [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide;

2- (acetylamino) -N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carbox amides;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide;

N-6- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide;

2-acetyl-N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxamide;

Methyl 6-{[1- (6-methyl) -azabicyclo [2.2.2] oct-3-ylamino] carbonyl} furo [3,2-c] pyridine-2-carboxylate;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-vinylfuro [2,3-c] pyridine-5-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-ethynylfuro [2,3-c] pyridine-5-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-cyanofuro [2,3-c] pyridine-5-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-fluorofuro [2,3-c] pyridine-5-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-iodofuro [2,3-c] pyridine-5-carboxamide;

N- [1- (6-methyl-azabicyclo [2.2.2] oct-3-yl] -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide;

3- (acetylamino) -N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carbox amides;

N- [1- (6-methyl) azabicyclo [2.2.2] oct-3-yl] -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide;

N-5- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide;

N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-formylfuro [2,3-c] pyridine-5-carboxamide;

3-acetyl-N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxamide;

Methyl 5-{[1- (6-methyl) -azabicyclo [2.2.2] oct-3-ylamino] carbonyl} furo [2,3-c] pyridine-3-carboxylate;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-ethynylfuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-cyanofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-fluorofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-chlorofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-bromofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-iodofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide;

2- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide;

N-6- [1- (6-methyl) azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide;

2-acetyl-N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide;

Methyl 6-[(2-azabicyclo [2.2.1] hept-5-ylamino) carbonyl] furo [3,2-c] pyridine-2-carboxylate;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-vinylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-ethynylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-cyanofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-fluorofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-iodofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide;

3- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide;

N-5- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -3-formylfuro [2,3-c] pyridine-5-carboxamide;

3-acetyl-N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide;

Methyl 5-[(2-azabicyclo [2.2.1] hept-5-ylamino) carbonyl] furo [2,3-c] pyridine-3carboxylate;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-ethynylfuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-cyanofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-fluorofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-chlorofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-bromofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-iodofuro [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide;

2- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide;

N-6- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide;

2-acetyl-N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide;

Methyl 6-[(2-azabicyclo [2.2.1] hept-6-ylamino) carbonyl] furo [3,2-c] pyridine-2-carboxylate;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-vinylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-ethynylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-cyanofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-fluorofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-iodofuro [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide;

3- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide;

N-5- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide;

N- (2-azabicyclo [2.2.1] hept-6-yl) -3-formylfuro [2,3-c] pyridine-5-carboxamide;

3-acetyl-N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide; or

Methyl 5-[(2-azabicyclo [2.2.1] hept-6-ylamino) carbonyl] furo [2,3-c] pyridine-3-carboxylate.

A compound of formula (I) which is any free compound or combination of

N- (1-azabicyclo [2.2.1] hept-3-yl) thieno [3,4-c] pyridine-6-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) thieno [3,4-c] pyridine-6-carboxamide;

N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,4-c] pyridine-6-carboxamide; or

N- (1-azabicyclo [3.2.2] non-3-yl) thieno [3,4-c] pyridine-6-carboxamide.

A compound of formula (I) which is any free compound or combination of

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) thieno [3,4-c] pyridine-6-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) thieno [3,4-c] pyridine-6-carboxamide; or

N- (2-azabicyclo [2.2.1] hept-6-yl) thieno [3,4-c] pyridine-6-carboxamide.

A compound of formula (I) which is any free compound or combination of

N- (1-azabicyclo [2.2.1] hept-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide;

N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide;

N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide;

N- (1-azabicyclo [3.2.2] non-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide;

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] [1] benzofuro [2,3-c] pyridine-3-carboxamide; or

N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] [1] benzothieno [2,3-c] pyridine-3-carboxamide.

A compound of formula (I) which is any free compound or combination of

N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide;

N- (2-azabicyclo [2.2.1] hept-5-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; or

N- (2-azabicyclo [2.2.1] hept-6-yl) -benzothieno [3,2-c] pyridine-3-carboxamide.

Additional embodiments of the invention include pharmaceutical compositions containing the compounds of the invention, the active compounds as free bases or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, and methods of treating identified diseases.

In another aspect, the present invention encompasses treating mammals suffering from schizophrenia or psychosis by administering a compound of Formula I in combination with an antipsychotic drug (also referred to as an antipsychotic). Compounds of the invention and antipsychotic drugs can be administered simultaneously or at separate intervals. When administered simultaneously, the compounds of the present invention and antipsychotic drugs can be incorporated into a single pharmaceutical composition. Alternatively, two separate compositions may be administered simultaneously, one containing the compound of the invention and the other containing the antipsychotic drug.

A further embodiment of the invention provides a method comprising administering to a mammal a therapeutically effective amount of a compound of the invention or a pharmaceutical composition containing said compound.

The present invention also encompasses pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Pharmaceutical compositions are administered rectally, topically, orally, sublingually or parenterally at therapeutically effective intervals. The pharmaceutical composition is administered to deliver a compound of the invention in an amount of about 0.001 to about 100 mg per kg of body weight of the mammal per day. In addition, the pharmaceutical composition is administered to deliver a compound of the present invention in an amount of about 0.1 to about 50 mg per kg body weight of the mammal per day.

A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, antipsychotic and a pharmaceutically acceptable excipient thereof. Pharmaceutical compositions are administered to independently administer the compound and the agent rectally, topically, orally, sublingually or parenterally, at therapeutically effective intervals. The pharmaceutical composition is administered to deliver a compound of the invention in an amount of about 0.001 to about 100 mg per kg of body weight of the mammal per day. In addition, the pharmaceutical composition is administered to deliver a compound of the present invention in an amount of about 0.1 to about 50 mg per kg body weight of the mammal per day.

The present invention also provides a compound according to formula (I) or a pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of a disease or condition in which a mammal will be alleviated by administration of a therapeutically effective amount of a7 nicotinic acetylcholine receptor agonist. The use of possible salts.

The present invention also provides a compound according to formula (I) or a pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of a disease or condition in which a mammal will be alleviated by administration of a therapeutically effective amount of a7 nicotinic acetylcholine receptor agonist. Possible salts, wherein the disease or condition is any one or more of the following diseases or a combination of the following diseases: symptoms of cognitive and attention deficits in Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease, dementia (mild) Cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, general anxiety disorder, post-traumatic stress disorder, mood and emotional disorders, amyotrophic lateral sclerosis, borderline personality disorder, Traumatic brain injury, behavioral and cognitive problems associated with common and brain tumors, AIDS dementia, complications Dementia associated with dementia, dementia associated with Lewy body, Huntington's disease, Parkinson's disease, delayed dyskinesia, pick disease, morbidity and food withdrawal control including anorexia nervosa, withdrawal symptoms associated with quitting smoking and dependent drug discontinuation, Tourette syndrome, age-related macular degeneration, glaucoma, neurodegeneration or pain associated with glaucoma.

In addition, the present invention is directed to symptomatic relief of a mammal by administration of an a7 nicotinic acetylcholine receptor agonist, comprising administering to the mammal a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof. Methods of treating a disease or condition in a mammal in need thereof.

The present invention also provides a method of treating a disease or condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof. Wherein the disease or condition is any one or more of the following diseases or a combination of the following diseases: symptoms of cognitive and attention deficits in Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease, elderly dementia (mild cognitive impairment), Senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, general anxiety disorder, posttraumatic stress disorder, mood and emotion disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, Behavioral and cognitive problems associated with common and brain tumors, AIDS dementia complications, dementia associated with Down syndrome, leu Sieve-related dementia, Huntington's disease, Parkinson's disease, delayed dyskinesia, PEEK disease, dysregulation of food intake, including morbidity and anorexia nervosa, withdrawal symptoms associated with quitting smoking and dependent drug discontinuation, Gilles de la Tourette syndrome, age- Associated macular degeneration, glaucoma, neurodegeneration or pain associated with glaucoma.

Compounds of formula I (azabicyclo is I) have optically active centers on the quinuclidin ring. Compounds of the present invention include quinuclidins in a 3R configuration and also include racemic mixtures, individual stereoisomers and compositions of various stoichiometric purity. For example, compounds of formula (I) include compounds having, but not limited to, the following stereospecificities.

Compounds of formula (I) (azabicyclo is II) have optically active center (s) at C3 and C4 on the [2.2.1] azabicyclic ring. The scope of the present invention is directed to racemic mixtures of various stoichiometric purity, individual stereoisomers and compositions of various stoichiometric purity, consisting of the following formula (I): endo-4S, endo-4R, exo-4S, exo-4R Contains:

The endo isomer is an isomer in which a non-hydrogen substituent in C3 of the [2.2.1] azabicyclic compound is projected to the larger of the two residual bridges. Exo isomers are isomers in which the non-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound is projected to the smaller of the two residual bridges. Thus, separate isomers of exo-4 (R), exo-4 (S), endo-4 (R) and endo-4 (S) may be present.

Compounds of formula (I) (azabicyclo III) have optically active center (s) at C1, C4 and C5 on the [2.2.1] azabicyclic ring. The scope of the present invention is of the various stoichiometric purity, consisting of formula (I) which is (1R, 4R, 5S), (1R, 4R, 5R), (1S, 4S, 5R), (1S, 4S, 5S) Racemic mixtures, individual stereoisomers and compositions of various stoichiometric purity are included:

The endo isomer is an isomer in which the non-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound is projected to the larger of the two residual bridges. Exo isomers are isomers in which the non-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound is projected to the smaller of the two residual bridges. Thus, there may be four separate isomers, exo- (1R, 4R, 5S), exo- (1S, 4S, 5R), endo- (1S, 4S, 5S), endo- (1R, 4R, 5R). .

Compounds of formula (I) (azabicyclo IV) have optically active center (s) at C1, C4 and C6 on the [2.2.1] azabicyclic ring. The scope of the invention is defined by Formula I, wherein exo- (1S, 4R, 6S), exo- (1R, 4S, 6R), endo- (1S, 4R, 6R) and endo- (1R, 4S, 6S) Consisting of racemic mixtures of varying stoichiometric purity, individual stereoisomers and compositions of varying stoichiometric purity:

The endo isomer is an isomer in which a non-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound is projected to the larger of the two residual bridges. The exo isomer is the isomer in which the non-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound is projected to the smaller of the two residual bridges. Thus, four separate isomers are included: exo- (1S, 4R, 6S), exo- (1R, 4S, 6R), endo- (1S, 4R, 6R) and endo- (1R, 4S, 6S).

Compounds of formula (I) (azabicyclo V) have optically active center (s) at C3 and C5 on the [3.2.1] azabicyclic ring. The scope of the present invention consists of racemic mixtures of varying stoichiometric purity, individual stereoisomers and consisting of Formula (I) which is endo-3S, 5R, endo-3R, 5S, exo-3R, 5R, exo-3S, 5S described below. Compositions of various stoichiometric purity include:

Compounds of formula (I) (azabicyclo VI) have optically active centers on [3.2.2] azabicyclic rings where one center is C3 when R ₂ is absent. The scope of the present invention encompasses racemic mixtures of varying stoichiometric purity, individual stereoisomers and compositions of varying stoichiometric purity, consisting of Formula I of the following 3 (S) and 3 (R):

Compounds of the present invention with specific stoichiometry have different activities and one isomer may be preferred over the other isomer for a given value set for various substituents. It is desirable that the stoichiometric purity is as high as possible, but absolute purity is not required. When azabicyclo is substituted with amides / thioamides alone or with substituents other than amides / thioamides (eg, R ₂ is alkyl), the present invention encompasses racemic mixtures and compositions of various stoichiometric purity . When referring to racemic mixtures and compositions, this means racemic mixtures and compositions of various stoichiometric purity. It is preferred to perform stereoselective synthesis and / or to purify the reaction product appropriately to produce substantially enantiomeric material. Suitable stereoselective synthetic procedures for producing enantiomeric pure materials are known in the art as a procedure for purifying racemic mixtures into enantiomeric pure fractions.

Stereoselective synthesis and / or reaction products are subjected to appropriate purification steps to produce substantially enantiomeric material. Suitable stereoselective synthetic procedures for producing enantiomeric pure materials are known in the art as a procedure for purifying racemic mixtures into enantiomeric pure fractions.

Another embodiment of a compound of Formula (I) includes one or more of the following arrangements or combinations of the following arrangements for the compound.

here,

in (i) the compound is a racemic mixture,

In (ii) the compound has an R stereochemistry at C-3 as disclosed herein and the stereochemistry at C-6 is not specific.

Other embodiments of compounds of Formula (I) include one or more of the following arrangements or combinations of the following arrangements for the compound.

here,

in (i) k ₂ is 0 (R ₂ is absent);

in (ii) R ₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl;

in (iii) R ₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl;

Part 2.2.1 in (iv) has exo-4 (S) stereochemistry as disclosed herein.

Another embodiment of a compound of Formula (I) includes one or more of the following arrangements or combinations of the following arrangements for the compound.

here,

in (i) R _2-3 is H;

in (ii) R _2-3 is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl;

R _2-3 in (iii) is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl.

Another embodiment of a compound of Formula (I) includes one or more of the following arrangements or combinations of the following arrangements for the compound.

here,

in (i) R _2-3 is H;

in (ii) R _2-3 is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl;

R _2-3 in (iii) is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl.

Another embodiment of a compound of Formula (I) includes one or more of the following arrangements or combinations of the following arrangements for the compound.

here,

in (i) k ₅ is 0 (R ₂ is absent);

R ₂ is absent when the stereochemistry of the azabicyclo in (ii) is 3R, 5R;

(iii) when R _2-a is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl and R _2-b is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or For aryl k ₅ is 2;

k ₅ is 1 when in (iv) R ₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl;

in (v) k ₅ is 1 when R ₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl.

Another embodiment of a compound of Formula (I) includes one or more of the following arrangements or combinations of the following arrangements for the compound.

here,

in (i) k ₆ is 0 (R ₂ is absent);

in (ii) each R _2-a is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl and each R _2-b is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cyclo K ₆ is 2 when alkyl or aryl;

k ₆ is 1 when ( ₂ ) R ₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl;

k ₆ is 1 when R ₂ in (iv) is F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl.

Further aspects and embodiments of the invention may be apparent to those skilled in the art in view of the following detailed description in conjunction with the examples and the appended claims. It is to be understood that the invention is capable of various forms of embodiment, and that the embodiments of the invention described below are intended to illustrate the disclosure of the invention and are not intended to limit the invention to the specific embodiments described herein.

Nicotinic acetylcholine receptor (nAChR) plays a large role in central nervous system (CNS) activity. In particular, it is known to relate to cognition, learning, mood, emotions and neuroprotection. There are several types of nicotinic acetylcholine receptors, each of which appears to play several roles in regulating CNS function. Nicotine acts on all these receptors and has a variety of activities. Unfortunately, not all activities are desirable. In fact, one of the most undesirable properties of nicotine is its low addictiveness and low ratio between efficacy and safety. The present invention relates to molecules having a greater effect on α7 nAChR than other closely related elements of this ligand-gate receptor family. Thus, the present invention provides compounds that are active drug molecules with fewer side effects.

Surprisingly, we have found cognitive and attention deficit symptoms of Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease, dementia (mild cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, Mood and emotional disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down syndrome, dementia associated with Lewy body, Huntington's disease, depression, common Anxiety disorders, age-related macular degeneration, Parkinson's disease, delayed dyskinesia, PEEK disease, posttraumatic stress disorder, difficulty in controlling food intake, including morbidity and anorexia nervosa, withdrawal symptoms associated with quitting smoking and dependent drug discontinuation, Of any one or combination of Tourette syndrome, glaucoma, neurodegeneration or pain associated with glaucoma Compounds of formula (I) or pharmaceutical compositions, pharmaceutically acceptable salts, racemic mixtures, or pure enantiomers thereof, useful for treatment have been found:

<Formula I>

Wherein azabicyclo is

ego;

W is

This,

Provided that the bond between the —C (═X) —group and the W group can be attached to any available carbon atom in the W group as shown in R ₃ , R ₆ and R ₁₅ ;

X is O or S;

R ₀ is H, lower alkyl, substituted lower alkyl or halogenated lower alkyl;

Lower alkyl is a straight and branched chain moiety of 1 to 4 carbon atoms;

Halogenated lower alkyl is lower alkyl having 1 to (2n + 1) substituent (s) independently selected from F, Cl, Br or I, where n is the maximum number of carbon atoms in the moiety;

Substituted lower alkyl has 0 to 3 substituents independently selected from F, Cl, Br or I, -CN, -NO ₂ , -OR ₁₀ , -SR ₁₀ , -NR ₁₀ R ₁₀ , -C (0 ) R ₁₀ , -C (0) OR ₁₀ , -C (S) R ₁₀ , -C (0) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) R ₁₀ , -S (O) R ₁₀ , -S (O) ₂ R ₁₀ , -OS (O) ₂ R ₁₀ , -S (O) ₂ NR ₁₀ R ₁₀ , -NR _1O S (O) ₂ is lower alkyl further having one substituent selected from R ₁₀ , phenyl and R ₁₈ and further one substituent selected from phenyl having 0 to 3 substituents selected from F, Cl, Br or I;

Each R ₁ is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl or substituted naphthyl;

Alkyl is a straight and branched chain moiety having 1 to 6 carbon atoms;

Halogenated alkyl is an alkyl moiety having 1 to 6 carbon atoms having 1 to (2n + 1) substituent (s) independently selected from F, Cl, Br or I, where n is the maximum carbon atom number of the moiety ;

Cycloalkyl is a cyclic alkyl moiety having 3 to 6 carbon atoms;

Substituted phenyl is phenyl having 1 to 4 substituents independently selected from each other from F, Cl, Br or I, or 1 substituent selected from R ₁₂ and 0 to 3 substituents selected from F, Cl, Br or I Retained phenyl;

Substituted naphthyl is naphthyl having 1 to 4 substituents independently selected from independently selected from F, Cl, Br or I, or one substituent selected from R ₁₂ and independently from F, Cl, Br or I A naphthalene moiety having 0 to 3 substituents selected, wherein the substitution may be independent on only one ring or on both rings of the naphthalene moiety;

Each R ₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, aryl, F, Cl, Br, I or R ₂ is absent when k ₂ , k ₅ or k ₆ is 0;

R _2-3 is H, alkyl, substituted alkyl, halogenated alkyl, F, Cl, Br or I;

Substituted alkyls have 0 to 3 substituents independently selected from F, Cl, Br or I, and R ₇ , R ₉ , -CN, -NO ₂ , -OR 1 _O , -SR _1O , -NR ₁₀ R ₁₀ , -C (O) R ₁₀ , -C (O) OR ₁₀ , -C (S) R ₁₀ , -C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) R ₁₀ , -S (O) R ₁₀ , -S (O) ₂ R ₁₀ , -OS (O) ₂ R ₁₀ , -S (O) ₂ NR ₁₀ R ₁₀ , -NR Further has one substituent selected from ₁₀ S (O) ₂ R ₁₀ , phenyl or R ₁₈ and further one substituent selected from phenyl having 0 to 3 substituents independently selected from F, Cl, Br or I An alkyl moiety of 1 to 6 carbon atoms;

k ₂ is 0 or 1;

k ₅ and k ₆ are independently 0, 1 or 2;

A --- A '--- A "is N (R ₄ ) -C (R ₃ ) = C (R ₃ ), N = C (R ₃ ) -C (R ₁₅ ) ₂ , C (R ₃ ) = C (R ₃ ) -N (R ₄ ), C (R ₃ ) ₂ -N (R ₄ ) -C (R ₃ ) ₂ , C (R ₁₅ ) ₂ -C (R ₃ ) = N, N ( R ₄ ) -C (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -C (R ₃ ) ₂ -N (R ₄ ), OC (R ₃ ) = C (R ₃ ), OC (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -0-C (R ₃ ) ₂ , C (R ₃ ) = C (R ₃ ) -O, C (R ₃ ) ₂ -C (R ₃ ) ₂ -0, SC (R ₃ ) = C (R ₃ ), SC (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -SC (R ₃ ) ₂ , C (R ₃ ) = C (R ₃ ) -S or C (R ₃ ) ₂ -C (R ₃ ) ₂ -S;

Each R ₃ is independently a bond with the core molecule, provided that only R ₃ is the bond and R ₆ or R ₁₅ is not such a bond, H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted Alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, -CN, -N0 ₂ , F, Br, Cl, I, -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -S (O) ₂ R ₁₉ , -C (O) R ₁₉ , -CO ₂ R ₁₉ , aryl, R ₇ or R ₉ ;

Aryl is phenyl, substituted phenyl, naphthyl or substituted naphthyl;

Alkenyl is a straight and branched chain portion of 2 to 6 carbon atoms having one or more carbon-carbon double bonds;

Halogenated alkenyl is an unsaturated alkenyl moiety having 2 to 6 carbon atoms having 1 to (2n-1) substituent (s) independently selected from F, Cl, Br or I, where n is the maximum carbon of the moiety Number of atoms;

Substituted alkenyl has 0 to 3 substituents independently selected from F or Cl, and R ₇ , R ₉ , -CN, -NO ₂ , -OR ₁₀ , -SR ₁₀ , -NR ₁₀ R ₁₀ , -C (O) R ₁₀ , -C (O) OR ₁₀ , -C (S) R ₁₀ , -C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) R ₁₀ , -S (O) R ₁₀ , -S (O) ₂ R ₁₀ , -OS (O) ₂ R ₁₀ , -S (O) ₂ NR ₁₀ R ₁₀ , -NR ₁₀ S ( O) a carbon atom further having one substituent selected from ₂ R ₁₀ , phenyl or R ₁₈ and further one substituent selected from phenyl having 0 to 3 substituents independently selected from F, Cl, Br or I Two to six unsaturated alkenyl moieties;

Alkynyl is a straight and branched chain portion of 2 to 6 carbon atoms having at least one carbon-carbon triple bond;

Halogenated alkynyl is an unsaturated alkynyl moiety having 3 to 6 carbon atoms having 1 to (2n-3) substituent (s) independently selected from F, Cl, Br or I, where n is the maximum carbon of the moiety Number of atoms;

Substituted alkynyl has 0 to 3 substituents independently selected from F or Cl, and R ₇ , R ₉ , -CN, -NO ₂ , -OR ₁₀ , -SR ₁₀ , -NR ₁₀ R ₁₀ , -C ( O) R ₁₀ , C (O) OR ₁₀ , -C (S) R ₁₀ , -C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) R ₁₀ , -S (O) R ₁₀ , -S (0) ₂ R ₁₀ , -OS (O) ₂ R ₁₀ , -S (O) ₂ NR ₁₀ R ₁₀ , -NR _1O S (O) ₂ carbon atoms further having one substituent selected from R ₁₀ , phenyl or R ₁₈ and further one substituent selected from phenyl having 0 to 3 substituents independently selected from F, Cl, Br or I To 6 unsaturated alkynyl;

Halogenated cycloalkyl is a cyclic moiety having 3 to 6 carbon atoms having 1 to 4 substituents independently selected from F or Cl;

Substituted cycloalkyl has 0 to 3 substituents independently selected from F or Cl, and R ₇ , R ₉ , -CN, -NO ₂ , -OR ₁₀ , -SR ₁₀ , -NR ₁₀ R ₁₀ , -C (O) R ₁₀ , -C (O) OR ₁₀ , -C (S) R ₁₀ , -C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) R ₁₀ , -S (O) R ₁₀ , -S (O) ₂ R ₁₀ , -OS (O) ₂ R ₁₀ , -S (O) ₂ NR ₁₀ R ₁₀ , -NR ₁₀ S ( O) a carbon atom further having one substituent selected from ₂ R ₁₀ , phenyl or R ₁₈ and further one substituent selected from phenyl having 0 to 3 substituents independently selected from F, Cl, Br or I Number 3 to 6 cyclic moieties;

Heterocycloalkyl is a cyclic moiety of 4 to 7 atoms, wherein one to two atoms in the ring are -S-, -N (R ₁₇ )-or -0-;

Halogenated heterocycloalkyl is a group of 4 to 7 atoms with 1 to 2 atoms in the ring, -S-, -N (R ₁₇ )-or -O-, having 1 to 4 substituents independently selected from F or Cl. Cyclic portion;

Substituted heterocycloalkyl has 0 to 3 substituents independently selected from F or Cl, and R ₇ , R ₉ , -CN, -N0 ₂ , -OR ₁₀ , -SR ₁₀ , -NR ₁₀ R ₁₀ , -C (O) R ₁₀ , -C (0) OR ₁₀ , -C (S) R ₁₀ , -C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) N (R ₁₀ ) ₂ , -NR ₁₀ C (O) R ₁₀ , -S (O) R ₁₀ , -S (0) ₂ R ₁₀ , -OS (O) ₂ R ₁₀ , -S (O) ₂ NR ₁₀ R ₁₀ , -NR ₁₀ S ( O) a ring further having one substituent selected from ₂ R ₁₀ , phenyl and R ₁₈ and further one substituent selected from phenyl having 0 to 3 substituents independently selected from F, Cl, Br or I 1 to 2 atoms in a -S-, -N (R ₁₇₎ - or -O- having 4 to 7 and the cyclic part of the atoms;

J, L, M and Q are N or C (R ₆ ), provided that only one of J, L, M or Q is N and the rest are C (R ₆ ), and further that the core molecule is a When attached to the denyl moiety Q is C (H) and additionally there is only one attachment to the core molecule;

G and Y are C (R ₆ ), provided that when the molecule is attached to the phenyl moiety in Y, G is CH;

R ₄ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R ₇ or R ₉ ;

Each R ₅ is independently H, lower alkyl or lower alkenyl;

Lower alkenyl is a straight and branched chain portion of 2 to 4 carbon atoms having at least one carbon-carbon double bond;

Each R ₆ is independently H, F, Br, I, Cl, -CN, -CF ₃ , -OR ₅ , -SR ₅ , -N (R ₅ ) ₂ or a bond to a core molecule, provided that only R ₆ Only one is said bond and R ₃ or R ₁₅ is not said bond);

V is selected from O, S or N (R ₄ );

R ₇ contains 1 to 3 heteroatoms independently selected from the group consisting of = N—, —N (R ₁₇ ) —, —O— and —S— in the ring, and 0 to 1 substituents selected from R ₁₈ Is a 5-membered heteroaromatic mono-cyclic moiety having 0 to 3 substituents independently selected from F, Cl, Br or I, or R ₇ is a 5-membered ring having the formula A 9-membered fused ring moiety having a fused 6-membered ring:

Wherein, G ₁ is O, S or NR ₁₇ ,

Wherein G is C (R ₁₆ ) or N, each G ₂ and G ₃ is independently selected from C (R ₁₆ ) ₂ , C (R ₁₆ ), O, S, N and N (R ₁₈ ) Provided that G ₂ and G ₃ are both O at the same time, S at the same time, or not O and S at the same time,

Wherein G is C (R ₁₆ ) or N, and each G ₂ and G ₃ are independently selected from C (R ₁₆ ) ₂ , C (R ₁₆ ), O, S, N and N (R ₁₇ ) , Each 9-membered fused ring moiety bears 0 to 1 substituents selected from R ₁₈ and further carries 0 to 3 substituent (s) independently selected from F, Cl, Br or I, wherein R _{The 7} moiety is attached to another substituent as defined in Formula (I) as valency is allowed at any position on any ring;

Each R ₈ is independently H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R ₇ , R ₉ , Phenyl or substituted phenyl;

R ₉ contains 1 to 3 heteroatoms selected from = N- in the ring, 0 to 1 substituents selected from R ₁₈ and 0 to 3 substituent (s) independently selected from F, Cl, Br or I Or a ₉ -membered heteroaromatic monocyclic moiety having 1 to 3 heteroatoms selected from = N-, including but not limited to, quinolinyl or isoquinolinyl in one or all two rings A 10-membered heteroaromatic bicyclic moiety containing 0, wherein each 10-membered fused ring moiety is 0-1 substituent selected from R ₁₈ and 0-3 independently selected from F, Cl, Br or I Bearing substituent (s) and having a bond attached directly or indirectly to the core atom when valence is permitted;

Each R ₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl, 1 substituent selected from a cycloalkyl, R ₁₃ is substituted by 1 substituent selected from alkyl, R ₁₃ is substituted by 1 substituent selected from R ₁₃ Substituted heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl or substituted phenyl;

Each R ₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl or halogenated heterocycloalkyl;

R ₁₂ is —N0 ₂ , —CN, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ or- NR ₁₁ S (O) ₂ R ₁₁ ;

R ₁₃ is -CN, -CF ₃ , -NO ₂ , -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ or -NR ₁₁ S (O) ₂ R ₁₁ ;

Each R ₁₄ is H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, -CN, -NO ₂ , -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -S (O) ₂ R ₁₉ , -C (O) R ₁₉ ,- CO ₂ R ₁₉ , aryl, R ₇ or R ₉ ;

Each R ₁₅ is independently alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, -CN, -NO ₂ , -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -C0 ₂ R ₁₉ , aryl, R ₇ , R ₉ or to a core molecule Only one R ₁₅ is said bond and R ₆ or R ₃ is not said bond;

Each R ₁₆ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, F, Cl, Br, I, -N0 ₂ , -CN, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ , -NR ₁₁ S (0) ₂ R ₁₁ or a bond attached directly or indirectly to a core molecule, provided that the bond to the core molecule in the 9-membered fused ring moiety is Only one, in addition, the fused ring moiety is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -NO ₂ , -C (O) NR ₁₁ R ₁₁ , -CN, -NR ₁₁ C (O) R ₁₁ , -S (O ) ₂ NR ₁₁ R ₁₁ or _{-NR 11 S (O) 2 R} 0 to 1 selected from ₁₁ Which may have a substituent, and have the additional, fused ring part is from 0 to 3 substituents selected from F, Cl, Br or I (s);

R ₁₇ has 1 substituent selected from H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, -SO ₂ R ₈ or R _{18 and} is selected from F, Cl, Br or Phenyl further having 0 to 3 substituents independently selected from I;

R ₁₈ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O ) NR ₁₁ R ₁₁ , -CN, -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ , -NR ₁₁ S (O) ₂ R ₁₁ , -NO ₂ , F, Cl, Br , Alkyl substituted with 1 to 4 substituent (s) independently selected from I or R ₁₃ , F, Cl, Br, cycloalkyl substituted with 1 to 4 substituent (s) independently selected from I or R ₁₃ , or Heterocycloalkyl substituted with 1 to 4 substituent (s) independently selected from F, Cl, Br, I or R ₁₃ ;

R ₁₉ is H, alkyl, cycloalkyl, substituted alkyl, halogenated alkyl, substituted phenyl or substituted naphthyl.

In another aspect, the present invention includes a method of treating a mammalian suffering from schizophrenia or psychosis by administering a compound of formula (I) in combination with an antipsychotic drug (also referred to as an antipsychotic). The compound of formula I and the antipsychotic drug may be administered simultaneously or at separate intervals. When co-administering a compound of formula (I) with an antipsychotic drug, they can be incorporated into a single pharmaceutical composition. Alternatively, two separate compositions may be administered simultaneously, one containing the compound of formula I and the other containing the antipsychotic drug.

The invention also encompasses the compounds of the invention, pharmaceutical compositions containing the active compounds and methods of treating identified diseases.

Abbreviations well known to those skilled in the art can be used (for example, "Ph" is phenyl, "Me" is methyl, "Et" is ethyl, "h" is hour, "min" is minute, "rt" is Room temperature).

All temperatures are in degrees Celsius.

Room temperature is in the range of 15 to 25 ° C.

AChR stands for acetylcholine receptor.

Elderly dementia is also known as mild cognitive impairment.

nAChR represents nicotinic acetylcholine receptor.

5HT ₃ R represents a serotonin-type 3 receptor.

α-btx represents α-bungarotoxin.

FLIPR is a device sold by Molecular Devices, Inc., designed to accurately measure intracellular fluorescence in high throughput whole cell assays (Schroeder et. Al., R Biomolecular Screening, 1 2), p 75-80, 1996]).

TLC stands for thin layer chromatography.

HPLC shows high pressure liquid chromatography.

MeOH stands for methanol.

EtOH stands for ethanol.

IPA stands for isopropyl alcohol.

THF stands for tetrahydrofuran.

DMSO stands for dimethyl sulfoxide.

DMF stands for dimethylformamide.

EtOAc stands for ethyl acetate.

Na ₂ S0 ₄ represents sodium sulfate.

K ₂ CO ₃ represents potassium carbonate.

MgSO ₄ represents magnesium sulfate.

If Na ₂ S0 ₄ , K ₂ CO ₃ or MgS0 ₄ is used as the desiccant, it is anhydride.

TMS stands for tetramethylsilane.

TEA stands for triethylamine.

DIEA stands for N, N-diisopropylethylamine.

MLA stands for methyllicaconitin.

Ether represents diethyl ether.

HATU represents O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate.

DBU stands for 1,8-diazabicyclo [5.4.0] undec-7-ene.

DPPA stands for diphenylphosphoryl azide.

50% saturated 1: 1 NaCl / NaHCO ₃ means a solution prepared by preparing a saturated solution of 1: 1 NaCl / NaHCO ₃ and adding the same volume of water.

CH ₃ SO ₂ Cl represents methanesulfonyl chloride.

Halogen is F, Cl, Br or I.

Non-exclusive examples of heteroaryl compounds included within the definitions of R ₇ and R ₉ include thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofura Nil, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, Isoquinolinyl, cinnaolinyl, indazolyl, indolinyl, phthalazinyl, feedridazinyl, triazinyl, isoindolinyl, furinyl, oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzo Thiazolyl, quinazolinyl, quinoxalinyl, naftridinyl, furopyridinyl, pyrrolopyridinyl or thienopyridinyl. All isomeric forms of the non-inclusive part named above include, for example, 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5- 1,1-benzofuran-6-yl, 1-benzofuran-7-yl, 2-benzofuran-1-yl, 2-benzofuran-2-yl, 2-benzofuran-3-yl, 2-benzo Benzofuranyl, including furan-4-yl or 2-benzofuran-5-yl. Non-inclusive examples R ₇ and R ₉ may be substituted as permitted within the definition of R ₇ and R _9, respectively, if valency permits. Those skilled in the art can identify acceptable substitutions by comparing the non-inclusive examples with the definitions of R ₇ and R _9, respectively.

Non-inclusive examples of heterocycloalkyl include tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino, piperidino, piperazine, azetidino, azetidinono, oxindolo, dihydroimi Dazolo, including but not limited to pyrrolidino or isoxazolinyl.

The carbon atom content of the various hydrocarbon containing moieties is indicated by a prefix meaning the minimum and maximum number of carbon atoms in the moiety, ie the prefix C _ij denotes a moiety comprising integer "i" to integer "j" carbon atoms. Thus, for example, C _1-6 alkyl refers to alkyl having 1 to 6 carbon atoms.

The core molecule is the following azabicyclo -N (R ₁ ) -C (= X)-.

Some of the amines described herein require the functionalization of the desired nitrogen using amine-protecting groups. Those skilled in the art will recognize the use of such protecting groups in synthetic schemes. Amino protecting groups include but are not limited to carbobenzyl oxy (CBz), tert-butoxy carbonyl (BOC), and the like. Examples of other suitable amino protecting groups are known to those skilled in the art and can be found in Protective Groups in Organic synthesis, 3rd Edition, written by Theodora Greene and Peter Wuts.

Mammals represent humans and other mammals.

Brine represents saturated aqueous sodium chloride solution.

Equ means the molar amount.

IR represents near infrared spectroscopy.

Lv represents a leaving group in the molecule, including Cl, OMe, OEt or mixed anhydrides.

Parr represents the name of the company selling the jar used to carry out the reaction under pressure.

PSI means pounds per square inch.

NMR represents nuclear (proton) magnetic resonance spectroscopy, and chemical shifts are reported in ppm (δ) downfield from TMS

MS represents mass spectrometry in m / e or mass / charge units. HRMS stands for high resolution mass spectrometry, expressed in m / e or mass / charge units. M + H ⁺ represents the cation which added the hydrogen atom to the parent molecule. MH ⁻ represents an anion obtained by subtracting a hydrogen atom from a parent molecule. M + Na ⁺ represents the cation which added the sodium atom to the parent molecule. M + K ⁺ represents the cation which added the potassium atom to the parent molecule. EI represents an electron impact. ESI stands for electrospray ionization. CI represents chemical ionization. FAB represents fast atomic collisions.

The compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases, and salts prepared from inorganic and organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, ferric iron, ferrous iron, lithium, magnesium, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines such as arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, Salts such as histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and the like do. Salts derived from inorganic acids include salts such as hydrochloric acid, bromic acid, iodic acid, sulfuric acid, phosphoric acid, phosphorous acid and the like. Salts derived from pharmaceutically acceptable non-toxic organic acids include C _1-6 alkyl carboxylic acids, dicarboxylic acids and tricarboxylic acids such as acetic acid, propionic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, adipic acid. And salts of citric acid and aryl and alkyl sulfonic acids such as toluene sulfonic acid.

As used herein, the term “effective amount” of a compound means an amount of compound (s) that is nontoxic but sufficient to provide the desired effect. As will be pointed out below, the exact requirements will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the disease to be treated, the particular compound (s) used, the mode of administration, and the like. Therefore, it is impossible to specify the exact "effective amount". However, an appropriate effective amount can be determined by those skilled in the art using only conventional experiments.

Dosage regimens for therapeutically effective amounts of the compound (s) to be administered and for the disease state to be treated with the compounds and / or compositions of the present invention may include a variety of factors including the age, weight, sex and medical condition of the subject, the severity of the disease, The route and frequency of administration and the particular compound (s) used may vary widely. The composition contains known carriers and excipients in addition to the therapeutically effective amount of the compound of formula (I). The pharmaceutical composition may contain the active ingredient in the range of about 0.001 to 100 mg / kg / day for adults and about 0.1 to 50 mg / kg / day for adults. About 1 to 1000 mg of active ingredient may be suitable as the daily dosage for adults. The daily dose may be administered 1 to 4 times a day.

In addition to the compound (s) of formula (I), the composition for therapeutic use may also comprise one or more nontoxic pharmaceutically acceptable carrier materials or excipients. As used herein, the term "carrier" material or "excipient" means any material that is not the therapeutic agent itself, and is used as a carrier and / or diluent and / or adjuvant, or vehicle for delivery of the therapeutic agent to a subject. Or in separable articles such as capsules or tablets suitable for oral administration, or for improving the handling or storage properties, or adding to the pharmaceutical composition to allow or promote the formation of composition dosage units. Excipients include, for example, improving the appearance of diluents, disintegrants, binders, adhesives, wetting agents, polymers, lubricants, lubricants, materials added to mask or neutralize unpleasant tastes or flavors, flavors, dyes, fragrances, and compositions. Materials added to do so may be included but are not limited thereto. Acceptable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, triceric acid, magnesium stearate, magnesium oxide, sodium and potassium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, Sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation to provide dispersion of the active compound in hydroxypropylmethyl cellulose or other methods known to those skilled in the art. For oral administration, the pharmaceutical compositions may be formed, for example, in the form of tablets, capsules, suspensions or solutions. If desired, other active ingredients may be included in the composition.

In addition to the oral administration described above, the compositions of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition applied to said route and in an effective dosage for the desired treatment. The composition can be administered, for example, parenterally, for example intravascular, intraperitoneal, subcutaneous or intramuscular. For parenteral administration, saline solution, dextrose solution or water can be used as a suitable carrier. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. Such solutions and suspensions may be prepared from sterile powders or granules containing one or more of the carriers or diluents mentioned for the preparation for oral administration. The compound can be dissolved in water, polyethylene glycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvants and modes of administration are widely well known in the pharmaceutical arts.

Serotonin type 3 receptor (5HT ₃ R) is a superfamily member of ligand-gate ion channels, including muscle and neuron nAChR, glycine receptor and γ-aminobutyric acid type A receptor. Like other members of the receptor superfamily, 5HT ₃ R exhibits high sequence homology with α7 nAChR, but the two ligand-gate ion channels are functionally very different. For example, α7 nAChR is rapidly inactivated, very permeable to calcium, and activated by acetylcholine and nicotine. Conversely, 5HT ₃ R is slowly inactivated, relatively non-permeable to calcium, and activated by serotonin. These experiments show that the α7 nAChR and 5HT ₃ R proteins have some homology, but work very differently. Indeed, the channels are very different pharmacologically. For example, Ondansetron, a highly selective 5HT ₃ R antagonist, has little activity at α7 nAChR. The opposite is also true. For example, GTS-21, a highly selective α7 nAChR agonist, has little activity in 5HT ₃ R.

α7 nAChR is a ligand-gate Ca ⁺⁺ channel formed with homopentamer of α7 subunit. In previous studies, α-Bungarotoxin (α-btx) selectively binds to the homopentamergic α7 nAChR subtype, and α7 nAChR has a high affinity for both α-btx and methyllicaconitine (MLA). It has been demonstrated to have a binding site. α7 nAChR is expressed at high levels in the hippocampus, ventral tegmental area and synergistic cholinergic projection from the nuclear bacilli to the sagittal cortex area. α7 nAChR agonists increase the release of neurotransmitters and improve cognition, awareness, attention, learning and memory.

Data from human and animal pharmacological studies have demonstrated that nicotinic cholinergic neural pathways regulate many important aspects of cognitive function, including attention, learning, and memory (Levin, ED, Psychopharmacology, 108: 417-). 31,1992; Levin, ED and Simon BB, Psychopharmacology, 138: 217-30, 1998]. For example, it is well known that nicotine enhances cognition and attention in humans. ABT-418, a compound that activates α4 β2 and α7 nAChR, enhances cognition and attention in clinical trials of Alzheimer's disease and attention-defective disorders (Potter, A. et. al., Psychopharmacology (Berl)., 142 (4): 334-42, Mar. 1999; Wilens, TE et. Al., Am. J. Psychiatry, 156 (12): 1931-7, Dec. 1999]. It is also apparent that nicotine and selective but weak α7 nAChR agonists enhance cognition and attention in rodents and non-human primates.

Schizophrenia is a complex multifactorial disease caused by genetic and non-genetic risk factors produced by a set of positive and negative symptoms. Positive symptoms include delusions and hallucinations, and negative symptoms include defects in emotion, attention, cognition and information processing. No single biological component in the disease appears to be a dominant pathogenic factor. Indeed, schizophrenia will be a syndrome that develops with a combination of many low decay risk factors. Pharmacological studies have demonstrated that dopamine receptor antagonists are effective in treating the apparent psychotic features (positive symptoms) of schizophrenia, such as hallucinations and delusions. Clozapine, an “atypical” antipsychotic drug, is novel because it is effective in treating both positive and some negative symptoms of the disease. Continued use of clozapine as a drug has very limited use, as it leads to the risk of increasing agranulocytosis and seizures. No other antipsychotic drugs are effective in treating the negative symptoms of schizophrenia. This is important because recovery of cognitive function is the best predictor of successful clinical and functional outcomes for schizophrenic patients (Green, M. F., Am J Psychiatry, 153: 321-30, 1996). In broad interpretation, it is clear that better drugs are needed to treat the disorder in order to restore the mental health of patients with cognitive impairment due to schizophrenia to a better state.

One aspect of cognitive deficits in schizophrenia can be measured using the auditory event-related potential (P50) test of the sensory gate. In this test, electroencepholographic (EEG) recording neuronal activity of the hippocampus can be used to measure the subject's response to a series of auditory "clicks" (Adler, LE et. Al. , Biol. Psychiatry, 46: 8-18, 1999]. The normal person responds to the second click to a greater degree than the first click. In general, schizophrenic and schizophrenic patients respond almost identically to two clicks (Cullum, C. M. et. Al., Schizophr: Res., 10: 131-41,1993). This data reflects the schizophrenic inability to "filter" or disregard unimportant information. Sensory gate defects are shown to be one of the important pathogenic features of the disease (Cadenhead, K. S. et. Al., Am. J. Psychiatry, 157: 55-9, 2000). Various studies have shown that nicotine normalizes sensory deficits in schizophrenia (Adler, L. E. et. Al., Am. J. Psychiatry, 150: 1856-61, 1993). Pharmacological studies have shown that the effect of nicotine on the sensory gate is via a7 nAChR (Adler, L. E. et. Al., Schizophr. Bull., 24: 189-202,1998). Indeed, biochemical data show that schizophrenic patients have less than 50% of the α7 nAChR receptor in the hippocampus, thus providing a theoretical interpretation of partial loss of function of α7 nAChR (Freedman, R. et. Al., Biol. Psychiatfry, 38: 22-33, 1995]. Interestingly, genetic data indicate that polymorphism in the promoter region of the α7 nAChR gene is highly associated with sensory gate defects in schizophrenia (Freedman, R. et. Al., Proc. Nat'l Acad. Sci. USA, 94 (2): 587-92, 1997; Myles-Worsley, M. et. Al., Am. J. Med. Genet, 88 (5): 544-50, 1999]. To date, no mutations in the α7 nAChR coding region have been identified. Thus, schizophrenia expresses the same α7 nAChR as in non-schizophrenia.

An optional α7 nAChR agonist can be found using a functional test on FLIPR (see WO 00/73431 A2). FLIPR is designed to read fluorescence signals from each well of a 96 or 384 well plate as fast as twice per second for up to 30 minutes. This assay can be used to accurately measure the functional pharmacology of α7 nAChR and 5HT ₃ R. To carry out the assay, cell lines expressing functional forms of α7 nAChR and cell lines expressing functional 5HT ₃ R are used, using α7 / 5-HT ₃ channels as drug targets. In both cases, ligand-gate ion channels were expressed in SH-EP1 cells. Both ion channels can produce strong signals in the FLIPR test.

The compounds of the present invention are α7 nAChR agonists and can be used to treat a wide range of diseases. For example, they can be used to treat schizophrenia or psychosis.

Schizophrenia is a multifaceted disease. Currently available drugs generally aim to modulate the positive aspects of schizophrenia, such as delusions. One drug, clozapine, targets a broader range of symptoms associated with schizophrenia. This drug has many side effects and is therefore unsuitable for many patients. Thus, there is a need for drugs to treat cognitive and attention deficits associated with schizophrenia. Similarly, there is a need for drugs to treat cognitive and attention deficits associated with schizophrenic disorders or similar symptoms found in patients with schizophrenia.

Psychosis is a mental disorder characterized by severely impaired patients' perception of reality. The patient suffers from delusions and hallucinations and can contradict when speaking. The patient's behavior can stumble and often do not understand the surroundings. In the past, the term psychosis has been applied to many states that conform to a less thorough definition than given above. For example, mood disorders were considered psychotic.

Various antipsychotic drugs exist. Conventional antipsychotic drugs include chloropromazine, flufenazine, haloperidol, roxapin, mesodazine, mollindon, perphenazine, pimozide, thiolidazine, thiotixene and trifluoroperazine. These drugs all have affinity for the dopamine 2 receptor.

These conventional antipsychotic drugs have several side effects, including sedation, weight gain, tremor, elevated prolactin levels, dyspepsia (exercise anxiety), dystonia, and muscle stiffness. Such drugs can also cause delayed dyskinesia. Unfortunately, only about 70% of schizophrenic patients respond to conventional antipsychotic drugs. For these patients, atypical antipsychotic drugs are useful.

Atypical antipsychotic drugs can generally alleviate the positive symptoms of psychosis, but may also cause negative psychotic symptoms to a higher extent than conventional antipsychotics. Such drugs can cause neurocognitive defects. Extrapyramidal (exercise) side effects may not occur with atypical antipsychotic drugs, so the atypical antipsychotic drugs have a low risk of developing delayed dyskinesia. After all, these atypical antipsychotic drugs produce little or no prolactin. Unfortunately, it is not without the side effects of these drugs. Each of these drugs produced different side effects (including agranulocytosis as a side effect group) but increased seizure risk, weight gain, lethargy, dizziness, tachycardia, reduced ejaculation volume and mild prolongation of the QTc interval.

In combination therapies for treating multiple symptoms of a disease such as schizophrenia, the compounds of formula (I) and antipsychotic drugs may be administered simultaneously or at separate intervals. When co-administering a compound of formula (I) with an antipsychotic drug, they may be incorporated into a single pharmaceutical composition, eg a pharmaceutical combination therapeutic composition. Alternatively, two separate compositions may be administered simultaneously, one composition containing a compound of formula (I) and the other composition containing an antipsychotic drug. In addition to the antipsychotic drugs listed above, examples of antipsychotic drugs include torazine, melaryl, trilapon, navan, stelazine, fermityl, prolicin, risperdal, ziplexa, seroquel, ZELDOX, aceto Phenazine, carfenazine, chlorproticsen, droperidol, roxapine, mesozinazine, molindon, ondansetron, pimozide, prochlorperazine and promazine.

Pharmaceutical combination therapeutic compositions can include a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of an antipsychotic drug. Such compositions may be formulated with common excipients, diluents or carriers and compressed into tablets, or formulated into elixirs or solutions for conventional oral or intramuscular intravenous administration. The compounds of the invention may be administered rectally, topically, orally, sublingually or parenterally, and may be formulated in sustained release dosage forms and the like.

For individual administration, a therapeutically effective amount of a composition containing a compound of formula (I) and an antipsychotic drug is administered on different schedules. After administering one, the other is administered, the time between the two administrations being extended by a therapeutically effective interval. The therapeutically effective interval may be initiated when (a) a compound of Formula (I) or (b) an antipsychotic drug is administered to a human so that the beneficial effect of the combination of (a) and (b) on the treatment of schizophrenia or psychosis The time period to reach the limit. The methods of administering the compounds of formula (I) and antipsychotic drugs can vary widely. Thus, one or both agents may be administered rectally, topically, orally, sublingually or parenterally.

As discussed, the compounds of the present invention are α7 nAChR agonists. Thus, according to another aspect of the present invention, the compounds of the present invention may be used in various forms, including cognitive and attention deficit symptoms of Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, elderly dementia (also known as mild cognitive impairment), and senile dementia. It can be used to treat diseases.

Alzheimer's disease, including cognitive and attention deficits, has multiple aspects. Currently, these defects are being treated with cholinesterase inhibitors. The inhibitor slows down the degradation of acetylcholine, increasing the activity of common nonspecific cholinergic nervous systems. Since drugs are nonspecific, they exhibit a wide range of side effects. Accordingly, there is a need for drugs that stimulate part of the cholinergic pathway and enhance the cognitive and attention deficits associated with Alzheimer's disease, without the side effects caused by nonspecific cholinergic pathway stimulation.

Neurodegeneration is a common problem associated with diseases such as Alzheimer's disease. Current drugs treat some of the symptoms of the disease, but they do not control the pathological pathology of the disease. Therefore, it would be desirable to provide a drug that can slow the progression of Alzheimer's disease.

Elderly dementia (mild cognitive impairment) is associated with memory impairment and otherwise intact cognitive function rather than attention deficit problems. Mild cognitive impairment is distinguished from senile dementia in that it involves the problem that memory loss with age is more persistent and difficult in patients with mild cognitive impairment. Since the identification of the disease is rather new, there are currently no drugs specifically identified for the treatment of mild cognitive impairment. Thus, there is a need for drugs to treat memory problems associated with mild cognitive impairment.

Geriatric dementia is not a single disease state. However, states classified under this name often include cognitive and attention deficits. In general, these defects are not treated. Thus, there is a need for drugs that improve cognitive and attention deficits associated with senile dementia.

As discussed, the compounds of the present invention are α7 nAChR agonists. Thus, other diseases to be treated with the compounds of the present invention include cognitive and attention deficits, attention deficit disorders, attention deficit hyperactivity disorders, depression, anxiety, general anxiety disorders, post-traumatic stress disorders, mood and emotion disorders, muscular dystrophy Sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems related to brain tumors, AIDS dementia complex, dementia related to Down syndrome, dementia related to Lewy body, Huntington's disease, Parkinson's disease, delayed dyskinesia, pick disease, pathology One or more of the following symptoms associated with difficulty controlling food intake, including overeating and anorexia, withdrawal symptoms associated with quitting smoking and dependent drug discontinuation, Gilles de la Tourette syndrome, age-related macular degeneration, glaucoma, neurodegeneration or pain associated with glaucoma, or Treating neurodegeneration associated with a combination thereof.

Attention deficit disorder has generally been treated with methylphenidate, an amphetamine-like molecule with some potential for abuse. Thus, it would be desirable to provide a drug that treats attention deficit disorder while having fewer side effects than currently used drugs.

Attention deficit hyperactivity disorder (also known as ADHD) is a neurobehavioral disorder that affects 3-5% of all American children. By interfering with humans' ability to continue work and suppress age appropriately, ADHD is related to cognition alone or to both cognitive and behavioral activities. Some types of ADHD exist as inattention subtypes, hyperactivity subtypes, and mixed subtypes. Treatment may include agents such as methylphenidate, dextroamphetamine or femoline, which act to reduce impulsiveness and hyperactivity and increase attention. There is currently no "treatment" for ADHD. Children with disabilities rarely overcome it and need appropriate medication.

Depression is usually a mood disorder that varies in duration from several months to more than two years and the degree of emotion includes sadness, despair and discouragement. Heterocyclic antidepressants (HCA) are currently the largest class of antidepressants, but monoamine oxidase inhibitors (MAOIs) are used for certain types of depression. Common side effects from HCA are sedation and weight gain. In addition, side effects from HCA in elderly patients with organic brain disease may include seizures and behavioral symptoms. The major side effect of using MAOI arises from food-drug interactions. Thus agents with fewer side effects will be useful.

Anxiety disorders (disorders that indicate significant anxiety or fear avoidance) represent areas in which the medical needs in the treatment of psychosis are inappropriate. See the Diagnostic & Statistical Manual of Mental Disorders, IV (1994), pp 393-394 on disease forms of various anxieties.

Common Anxiety Disorders (GADs) occur when a person is worried about things such as family, health or work even when there is no reason to worry and can't. About 3-4% of the US population annually suffers from GAD. GAD most often occurs in childhood or adolescents, but it can also occur in adults. This often affects women more than men. Currently, treatments include cognitive-behavioral therapies, relaxation techniques and biofeedback to regulate muscle tension and medications such as benzodiazepines, imipramine and buspyrone. The drugs are effective, but all of them are burdened with side effects. Accordingly, there is a need for pharmaceutical agents that have fewer side effects and treat symptoms.

Anxiety also includes post-traumatic stress disorder (PTSD), which is a form of anxiety caused by the memory of traumatic events that directly affect the patient or that the patient may have witnessed. The disorder generally affects survivors of traumatic events, including sexual assault, physical assault, war, torture, natural disasters, car accidents, plane accidents, hostage situations or mass executions. These pains can also affect those who have been rescued in plane accidents or mass kills, witnesses of traffic accidents, or those who have unexpectedly lost loved ones. Treatment of PTSD includes cognitive-behavioral therapies, group psychotherapy and drugs such as clonazepam, lorazepam and selective serotonin-reuptake inhibitors such as fluoxetine, sertraline, paroxetine, chitalopram and fluvox Min is included. The medicament aids in the control of anxiety and depression. Various forms of exposure therapy (eg, systematic desensitization and image association) can all be used in PTSD patients. Treatment of exposure to PTSD involves repeatedly reproducing the trauma under controlled conditions, assisting in promoting trauma progression. Thus, there is a need for better pharmaceutical agents to treat post-traumatic stress disorder.

Mood and emotional disorders include a broad group of diseases including unipolar depression and bipolar mood disorder. This disease has been treated with three major classes of compounds. The first group is heterocyclic antidepressants (HCA). This group includes well known tricyclic antidepressants. The second group of compounds used in the treatment of mood disorders are monoamine oxidase inhibitors (MAOIs) used in certain types of diseases. The third drug is lithium. Common side effects from HCA are sedation and weight gain. Side effects from HCA in elderly patients with organic brain disease also include seizures and behavioral symptoms. The main side effects of using MAOI arise from food-drug interactions. Positive side effects from lithium use include, but are not limited to, weight gain, vomiting, diarrhea, polyuria, following symptoms and tremors. Toxic side effects from lithium can include persistent headaches, conscious confusion, and can cause seizures and deep veins. Thus agents with less side effects and interaction with food or other agents will be useful.

Borderline personality disorder is also known as bipolar disorder, but borderline personality disorder is more common. People with borderline personality disorder have emotional control disorders. Pharmaceutical agents are used to treat specific symptoms such as depression or accident distortion.

Acquired immune deficiency syndrome (AIDS) results from infection with human immunodeficiency virus (HIV). The virus attacks selected cells and impairs the proper functioning of the immune, nervous and other systems. HIV infection can cause other problems, including but not limited to, for example, difficulty in accidents (also known as AIDS dementia complications). Therefore, there is a need for drugs that alleviate confusion and mental decline in people with AIDS.

Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease, belongs to a class of disorders known as motor neuron diseases, in which specific nerve cells in the brain and spinal cord progressively degenerate, negatively affecting the regulation of spontaneous movement. Although patients can be treated for some of their symptoms and Riluzole has been shown to prolong patient survival, there is currently no treatment for amyotrophic lateral sclerosis. Thus, there is a need for pharmaceutical agents for the treatment of such diseases.

A traumatic brain injury occurs when the brain is damaged by a sudden physical assault on the head. Symptoms of traumatic brain injury include confusion and other cognitive problems. Thus, there is a need to treat symptoms of confusion and other cognitive problems.

Brain tumors are abnormal growths of tissue found within the skull. Symptoms of brain tumors include behavioral and cognitive problems. Surgery, radiation, and chemotherapy are used to treat tumors, but other therapies are also needed to treat related symptoms. Thus, there is a need for pharmaceutical agents to treat symptoms of behavioral and cognitive problems.

People with Down's syndrome have a significant portion of extra chromosome 21 in all or at least some of these cells. Adults with Down syndrome are known to be dangerous for Alzheimer's type dementia. At present, the treatment for Down syndrome is not known. Therefore, there is a need to treat dementia associated with Down syndrome.

Genetic program degradation in certain areas of the brain causes Huntington's disease. Early symptoms of Huntington's disease include mood swings or learning of new things or difficulty in remembering facts. Most of the drugs used to treat the symptoms of Huntington's disease have side effects such as fatigue, anxiety, or overexertion. At present, no treatment exists to stop or reverse the progression of Huntington's disease. Accordingly, there is a need for pharmaceutical agents that have fewer side effects and treat symptoms.

Dementia associated with Lewy bodies is a neurodegenerative disorder involving abnormal structures known as Lewy bodies, found in certain areas of the brain. Symptoms of dementia-associated dementia include, but are not limited to, variable cognitive impairment with epilepsy delirium. Currently, treatment relates to treating Parkinson's disease symptoms and psychotic symptoms. However, drugs that control tremor or reduce muscle movement can actually exacerbate the near-term disease of dementia-related dementia. Thus, there is a need for pharmaceutical agents to treat dementia associated with Lewy bodies.

Parkinson's disease is a neurological disorder characterized by tremors, dyskinesia and muscular dystrophy. At present, there is no treatment to stop the progression of the disease. Thus, there is a need for pharmaceutical agents to treat Parkinson's disease.

Delayed dyskinesia is associated with the use of conventional antipsychotic drugs. This disease is most often characterized by involuntary movement, which is manifested by puckering of the lips and tongue and / or twisting of the arms or legs. The incidence of delayed dyskinesia due to drug exposure among patients receiving conventional antipsychotic drugs is about 5% per year. The appearance of about 2% of people with the disease is severely impaired by delayed dyskinesia. At present, there is no generalized treatment for delayed dyskinesia. In addition, eliminating drugs that produce effects is not always an option because of underlying problems. Accordingly, there is a need for pharmaceutical agents to treat symptoms of delayed dyskinesia.

Pick disease changes from personality by developing symptoms from the slow progressive degeneration of social skills and causing symptoms of loss of intelligence, memory and language. Common symptoms include memory loss, spontaneous defects, difficulty in thinking or concentrating, and speech impairment. At present, there are no specific treatments or treatments for pick disease, but some symptoms can be treated with cholinergic and serotonin-boosting antidepressants. In addition, antipsychotic medications may alleviate the symptoms of FTD patients who have experienced delusions or hallucinations. Thus, there is a need for pharmaceutical agents that treat progressive degeneration of social skills and treat symptoms with fewer side effects.

Difficulties in controlling food intake associated with eating diseases, including pathological and anorexia nervosa and anorexia nervosa, include neurophysiological pathways. It is difficult to treat anorexia nervosa because patients do not participate or remain after the program. At present, there is no effective treatment for people suffering from severe anorexia nervosa. Cognitive behavioral therapy assists patients with morbidity and anorexia; However, the response rate is about only 50% and current treatments do not adequately treat emotional control. Thus, there is a need for pharmaceutical agents to treat diseases underlying the neurophysiological problem of food intake control difficulties.

Tobacco smoking has long been recognized as a major public health problem. However, despite popular perceptions of health risks, smoking habits remain particularly persistent and difficult to break. There are many possible treatment options, but people continue to smoke. Transdermal administration of nicotine or chewing gum is a common treatment. However, nicotine has a number of side effects in vivo and has many side effects. It is clear that a convenient and relatively easy way to assist smokers by reducing or eliminating tobacco consumption requires and requires long-term patience. Drugs that can selectively stimulate only certain nicotinic receptors will be useful in smoking cessation programs.

The smoking cessation program can optionally include drugs to be administered orally. The drug may be in tablet form. However, it is desirable to administer the daily dose during waking hours by administering a series of incremental doses throughout the day. Preferred methods for such administration include slowly dissolving lozenges, troches or chewing gums that disperse the drug. Another drug for treating nicotine addiction is Zyban. This is not a nicotine replacement such as gum and patches. Rather, it acts on other areas of the brain and is effective in helping those who attempt to quit smoking adjust their nicotine aspiration or thoughts about tobacco use. Zyban is not very effective, so there is a need for effective drugs to assist smokers' desire to quit. Such drugs can be administered transdermally using skin patches. In certain cases, the drug may be administered by subcutaneous injection, especially when using sustained release formulations.

Drug use and addiction are complex phenomena that cannot be included within a single limitation. Different drugs have different effects and therefore different forms of intoxication. Two basic causes of drug addiction are tolerance and physical addiction. Tolerance exists when a user must produce in successively higher doses the effect that was originally achieved at a lower dose. Physical addiction exists when the user's physiological adaptation to the drug develops and withdrawal (ablation) syndrome is present when the drug is no longer ingested. Withdrawal syndrome can occur when the drug is discontinued or when the drug is replaced by an antagonist at the drug binding site of the cell receptor to neutralize its effects. Drug addiction does not always require physical addiction.

In addition, drug addiction often includes psychological addiction, i.e., a pleasant feeling or satisfaction when taking a drug. These feelings induce the user to repeat the drug experience or avoid discomfort due to drug ablation. Drugs that produce strong physical intoxication, such as nicotine, heroin and alcohol, are often abused and difficult to stop the pattern of intoxication. Addictive drugs act on the CNS, generally reducing anxiety and tension; To produce developmental, euphoric or other pleasant mood changes; Provide the user with emotions with increased mental and physical abilities; It changes sensory perception in some pleasant ways. Among the drugs that are commonly abused are ethyl alcohol, opioids, anti-anxiety agents, sleeping pills, cannabis (marijuana), cocaine, amphetamines and hallucinogens. Current treatments for drug-addicts often include a combination of behavioral therapies and drugs. Medications such as methadone or LAAM (levo-alpha-acetyl-methalol) are effective in inhibiting withdrawal symptoms and drug desires associated with anesthetic addiction, thus reducing illegal drug use and the opportunity for individuals to continue treatment. To increase. The first withdrawal method medically assisting in narcotic addiction is to have the patient replace with a similar drug that produces milder withdrawal symptoms, thereby gradually reducing the substitute drug. The most commonly used medication is methadone and is administered orally once daily. Patients start with the lowest dose to inhibit more severe withdrawal signals, then gradually reduce the dose. Sedatives may be used as a substitute for withdrawal. Patients can be replaced with long-acting sedatives, for example diazepam or phenobarbital, and then gradually decrease.

Gilles de La Tourette syndrome is a genetic neurological disorder. The disorder is characterized by unregulated speech ringing and involuntary behavior called tics. The symptoms generally appear in individuals before age 18. The behavioral disorder may begin with simple cramps and progress to multiple complex cramps including breathing and negative cramps. Voice cramps can begin with a growling or barking noise and progress to an obsessive vocalization. Obscenity (nonvoluntary fecal vocalization) occurs in 50% of patients. Severe cramps and obscenity can be physically and socially disabled. Cramps tend to be more complex than myoclonus, but less complex than martial arts, where they must be differentiated. Patients can spontaneously inhibit them for seconds or minutes.

At present simple convulsions are often treated with benzodiazepines. In simple and complex cramps, clonidine can be used. Long-term use of clonidine does not cause delayed dyskinesia; Its limited adverse effect is hypotension. In more severe cases, antipsychotics such as haloperidol may be required, but their use may be limited by side effects of discomfort, Parkinson's disease, dyspepsia and delayed dyskinesia caused by the antipsychotics. There is a need for a safe and effective method for treating the syndrome.

Age-related macular degeneration (AMD) is a common ocular disease that develops in the retinal macula, a small part of the macular that aids in the generation of the correct central vision required for "straight ahead" activities, including reading and driving. People with AMD lose their clear central vision. AMD has a wet form and a dry form. In dry AMD, the photosensory cells of the retinal macula are slowly degraded. There is currently no cure for dry AMD. In wet AMD, new and weak blood vessels grow under the retinal macula, as in aggravated dry AMD, and these vessels often lack blood and fluid, which quickly damages the macula and impairs central vision. Laser surgery can treat wet AMD in some cases. Thus, there is a need for pharmaceutical agents to treat AMD.

Glaucoma in the disease group results from an increase in intraocular pressure causing pathological changes in the optical disc, negatively affecting the field of vision. Medications for treating glaucoma reduce intraocular pressure by reducing the amount of fluid entering the eye or by increasing the drainage of fluid from the eye. However, current drugs have weaknesses that do not work over time or cause side effects, so the eye care professional prescribes other drugs or adjusts the prescription of the drug to be used. There is a need for a safe and effective method for treating problems caused by glaucoma.

During the ischemic period of glaucoma, exotoxin amino acids are released and stimulate the inducible form of nitric oxide synthase (iNOS), which causes neurodegeneration. Alpha 7 nicotinic agonists can stimulate the release of inhibitory amino acids, such as GABA, which will buffer overkinetics. Alpha 7 nicotinic agonists also protect nerves directly on nerve cell bodies. Thus, alpha 7 nicotinic agonists have the potential of neuroprotection in glaucoma.

People suffering from pain often have what appears to be "terrible triads" from pain, so that insomnia and sorrow develop and all of these suffer painful individuals and their families. Pain can take many forms, including but not limited to headaches of all severities, back pain, neuropathic pain, and pain from the presence of or other radiation conditions such as arthritis and cancer. The pain can be chronic (continuous pain for months or years) or acute (short-lived, immediate pain that distinguishes between persons suffering from possible injuries and in need of treatment). People with pain respond differently to individual therapies and vary in their success. There is a need for a safe and effective way to treat pain.

Finally, the compounds of the present invention can be used in combination therapy using orthopedic and atypical antipsychotic drugs (also referred to as antipsychotics). All compounds within the present invention can also be used with each other to prepare pharmaceutical compositions. The combination therapy reduces the effective dose of antipsychotic drugs and thus reduces the side effects of antipsychotic drugs. Some common antipsychotic drugs that can be used in the practice of the present invention include Haldol. Some atypical antipsychotic drugs include ziprasidone, olanzapine, resperidone, and quiediapine.

Compounds of formula (I) can be prepared as shown in Scheme 1. A key step in the preparation of this class of compounds is that the azabicyclic moiety is required in the presence of an activator with essential acid chlorides (Lv = Cl), mixed anhydrides (Lv = diphenyl phosphoryl, bis (2-oxo-3-oxazoli) Diyl) phosphinyl, or acyloxy of the formula OC (O) -R _Lv , wherein R _Lv comprises phenyl or t-butyl) or a carboxylic acid (Lv = OH). Suitable activators are known in the art, eg, Kiso, Y., Yajima, H., “Peptides” pp. 39-91, San Diego, CA, Academic Press, (1995). It is well known in the art and includes, but is not limited to, reagents such as carbodiimide, phosphonium and uronium salts (eg HATU).

Generally, acids are activated using HATU or converted to acyl azide using DPPA. Appropriate azabicyclo-amine is added to the appropriate activated acid or azide solution to afford the desired final compound. Or the acid is converted to mixed anhydride by treatment with bis (2-oxo-3-oxazolidinyl) phosphonic chloride in the presence of TEA in CH ₂ Cl ₂ or CHCl ₃ as solvent. The resulting anhydride solution is reacted directly with neatly added or appropriate amine added using DMF or aqueous DMF as solvent. In some cases, the ester (Lv is OMe or OEt) can be reacted directly with the amine in refluxed methanol or ethanol to obtain a compound of formula (I).

There are several ways in which amine precursors of azabicyclo I can be obtained. Certain 6-substituted- [2.2.2] -3-amines are known in the art. Methods for preparing compounds of azabicyclo I are described in Acta Pol. Pharm. 179-85 (1981). Alternatively, 6-substituted- [2.2.2] -3-amines can be prepared by reduction of the oxime or imine of the corresponding 6-substituted-3-quinuclidinone in a manner known to those skilled in the art. J. Labeled Compds. Radiopharm., 53-60 (1995), J. Med. Chem. 988-995, (1998), Synth.Commun. 1895-1911 (1992), Synth.Commun. 2009-2015 (1996) ] Reference). Alternatively, 6-substituted- [2.2.2] -3-amines are described in Synth. Commun. 1895-1911 (1995), after the Mitsunobu reaction, can be prepared from 6-substituted-3-hydroxyquinuclidin by deprotection. Alternatively, the 6-substituted- [2.2.2] -3-amine is converted to 6-substituted-3-hydroxyquinuclidin to the corresponding mesylate or tosylate, followed by J. Med Chem. 587-593 (1975), which may be prepared by substitution and reduction with sodium azide.

Oximes can be prepared by treating 3-quinuclidinone with hydroxylamine hydrochloride in the presence of a base. Imines can be prepared by treating 3-quinuclidinone with primary amines under dehydration conditions. 3-hydroxyquinuclidin can be prepared by reduction of 3-quinuclidinone. 6-Substituted-3-quinuclidinone can be prepared by known procedures (J. Gen. Chem. Russia 3791-3795, (1963), J. Chem. Soc. Perkin Trans. I409-420 (1991), J. Org. Chem. 3982-3996 (2000)).

Those skilled in the art will appreciate that the process described for the reaction of unsubstituted 3-amino-1-azabicyclo [2.2.1] heptane (azabicyclo II without R ₂ ) is substituted with a compound (R ₂ is present and not H). Will be equally applicable. Compounds in which R ₂ is not H can be prepared from suitably substituted nitro alcohols using the procedure described in Tetrahedron (1997), 53, p. 11121, as shown below. Methods of synthesizing nitro alcohols are well known in the art (see J. Am. Chem. Soc. (1947), 69, p 2608). The following scheme shows how to modify the synthesis of exo-3-amino-1-azabicyclo [2.2.1] heptane as the bis (hydro para-toluenesulfonate) salt described in detail herein to obtain an amine precursor. The desired salt can be prepared using standard procedures.

Compounds of azabicyclo II in which R ₂ is not H are also selected from the intermediates described in the synthesis of exo-3-amino-1-azabicyclo [2.2.1] heptane as the bis (hydro para-toluenesulfonate) salts described in detail herein. It can be produced by modification. For example, intermediate 6 can be oxidized to aldehyde using the procedure described in Tetrahedron (1999), 55, p 13899 and treated with an organometallic reagent to yield intermediate 20. Intermediate 20 can be converted to an amine using the method described for the synthesis of exo-3-amino-1-azabicyclo [2.2.1] heptane as a bis (hydro para-toluenesulfonate) salt. Once the amine is obtained, the desired salt can be prepared by standard procedures.

The scheme used is for the preparation of exo-3-amino-1-azabicyclo [2.2.1] heptane. However, the variants discussed can also be applied in the preparation of endo-isomers.

N- (2-azabicyclo [2.2.1] hept) -5-amine and 6-amine:

Here, Lv may be —CH ₂ Ph, —CH (Me) Ph, —OH, —OMe, or —OCH ₂ Ph.

Each of the amine precursors for azabicyclo III and azabicyclo IV can be prepared by reducing the oxime or imine of the corresponding N-2-azabicyclo [2.2.1] -heptanone by methods known to those skilled in the art (see [ J. Labeled Compds.Radiopharm., 53-60 (1995), J. Med. Chem. 988-995, (1998), Synth.Commun. 1895-1911 (1992), Synth.Commun. 2009-2015 (1996) ] Reference). Oximes can be prepared by treating N-2-azabicyclo [2.2.1] heptanone with hydroxylamine hydrochloride in the presence of a base. Imines can be prepared by treating N-2-azabicyclo [2.2.1] -heptanone with primary amines under dehydration conditions. N-2-azabicyclo [2.2.1] heptanone can be prepared by known procedures (Tet. Lett. 1419-1422 (1999), J. Med. Chem. 2184-2191 (1992), J Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995).

Those skilled in the art will also appreciate the methods described for the reaction of unsubstituted 1-azabicyclo [3.2.1] octane-3-amine or 1-azabicyclo [3.2.2] nonan-3-amine (without R ₂ ). It will be appreciated that it is equally applicable to substituted compounds (R ₂ is not H) (azabicyclo is V and VI, respectively). R ₂ substituents may be introduced via standard alkylation chemistry as is known to those skilled in the art. 1-azabicyclo [3.2.1] octan-3-one or 1-azabicyclo [3.2.2] nonan-3-one at 0 ° C. to −78 ° C. hindered amine in a solvent such as THF or ether, For example, after exposure to LDA (lithium diisopropylamide), alkylating agents (R ₂ Lv, where Lv = Cl, Br, I, OTs, etc.) are added, followed by warming to about 0 ° C. to room temperature, followed by aqueous post-treatment. The desired compound is obtained as a mixture of isomers. Chromatographic cleavage (flash, HPLC or chiral HPLC) will provide the desired purified alkylated ketone. This will provide the desired stereoisomer by formation of the oxime and subsequent reduction.

Thioamides can be prepared from essential thioesters by directly replacing thioesters with aminoazabicyclic compounds. Thioesters are described in J. Chem. Organometallic Chem., 95-98 (1987). One skilled in the art also knows Lawson's reagent (Lawesson's reagent, Lawesson et. Al. In Bull. Soc. Chim. Belg., 229 (1978)) or P ₄ S ₁₀ (Chenu. Rev., 45 (1961). It will be quickly seen that the compounds can be prepared from the amides exemplified herein by treatment with a reagent such as). Alternatively the dithiocarboxylic acid ester can be reacted with the corresponding amino-azabicyclo compound to form the same thioamide.

Preparation of Amine:

Synthesis of exo-3-amino-1-azabicyclo [2.2.1] heptane as bis (hydro para-toluenesulfonate) salt:

Step A. Preparation of 2- (benzoyloxy) -1-nitroethane (Intermediate 1)

Benzoyl chloride (14.9 mL, 128 mmol) was added to a stirred solution of nitroethanol (9.2 mL, 128 mmol) in anhydrous benzene (120 mL). The solution was refluxed for 24 h and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel. Elution with hexane-EtOAc (80:20) afforded intermediate 1 as a white solid (yield 68%): ¹ H NMR (CDCl ₃ ) δ 8.0, 7.6, 7.4, 4.9, 4.8.

Step B. Preparation of ethyl E-4- (benzylamino) -2-butenoate (intermediate 2).

Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, technical grade) was added to a stirred solution of benzylamine (16 mL, 146 mmol) in CH ₂ Cl ₂ (200 mL) at room temperature. . The reaction mixture was stirred for 15 minutes and diluted with ether (1 L). The mixture was washed with saturated aqueous NaHCO ₃ (3 ×) and water, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with hexane-EtOAc (70:30) gave intermediate 2 as a clear oil (yield 62%): ¹ H NMR (CDCl ₃ ) δ 7.4-7.2, 7.0, 6.0, 4.2, 3.8, 3.4, 2.1-1.8 , 1.3.

Step C. Preparation of trans-4-nitro-1- (phenylmethyl) -3-pyrrolidineacetic acid ethyl ester (Intermediate 3).

A solution of intermediate 1 (6.81 g, 34.9 mmol) and intermediate 2 (7.65 g, 34.9 mmol) in EtOH (70 mL) was stirred at rt for 15 h and then concentrated in vacuo. The residue was diluted with ether (100 mL) and saturated aqueous NaHCO ₃ (100 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel. Elution with hexane-EtOAc (85:15) gave intermediate 3 as a clear oil (yield 76%): ¹ H NMR (CDCl ₃ ) δ 7.4-7.3, 4.8-4.7, 4.1, 3.8-3.6, 3.3- 3.0, 2.7-2.6, 2.4-2.3, 1.2.

Step D. Preparation of trans-4-amino-1- (phenylmethyl) -3-pyrrolidineacetic acid ethyl ester (Intermediate 4).

A mixture of intermediate 3 (3.28 g, 11.2 mmol) and RaNi (15 g) in EtOH (100 mL) was placed in a Parr bottle and hydrogenated at room temperature under hydrogen (46 psi) atmosphere for 4 hours. The mixture was filtered through a pad of celite and the solvent removed in vacuo to yield intermediate 4 as a clear oil (yield 100%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.3-7.2, 4.1, 3.6, 3.2 , 3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.

Step E. Preparation of trans-4- (1,1-dimethylethoxycarbonylamido) -1- (phenylmethyl) -3-pyrrolidineacetic acid ethyl ester (Intermediate 5).

Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) was added to a stirred solution of intermediate 4 (2.94 g, 11.2 mmol) in CH ₂ Cl ₂ (30 mL) cooled in an ice bath. The reaction was warmed to rt and stirred overnight. The mixture was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel. Elution with hexane-EtOAc (80:20) gave intermediate 5 as a white solid (yield 77%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.4-7.2, 5.1-4.9, 4.1, 4.0-3.8 , 3.6, 3.2-3.0, 2.8-2.6, 2.5-2.4, 2.3-2.1, 1.4, 1.3.

Step F. Preparation of trans (tert-butoxycarbonylamino) -4- (2-hydroxyethyl) -1- (N-phenylmethyl) pyrrolidine (Intermediate 6).

LiAlH ₄ powder (627 mg, 16.5 mmol) was added in small portions to a stirred solution of intermediate 5 (3.0 g, 8.3 mmol) in dry THF (125 mL) in a −5 ° C. bath. The mixture was stirred in a -5 ° C bath for 20 minutes, then quenched by the addition of water (0.6 mL), 15% (w / v) aqueous NaOH (0.6 mL) and water (1.8 mL) sequentially. Excess anhydrous K ₂ CO ₃ was added and the mixture was stirred for 1 hour and then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc gave intermediate 6 as a white solid (yield 94%): ¹ H NMR (CDCl ₃ ) δ 7.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3.7, 3.3-3.2, 2.8-2.7 , 2.3-2.1, 1.7, 1.5.

Intermediate 6 is a racemic mixture that can be cleaved via chromatography using a Daicel chiral pack AD column. From the two enantiomers obtained, the corresponding enantiomerically pure exo-4-S final compound was obtained at (+)-enantiomer, [α] ²⁵ _D +35 (c 1.0, MeOH), whereas (-) In the enantiomer, [α] ²⁵ _D -34 (c 0.98, MeOH) an enantiomerically pure exo-4-R final compound was obtained which did not make a significant change to the method provided herein.

Step G. Preparation of exo 3- (tert-butoxycarbonylamino) -1-azabicyclo [2.2.1] heptane (Intermediate 7).

TEA (8.0 g, 78.9 mml) was added to a stirred solution of intermediate 6 (2.5 g, 7.8 mmol) in CH ₂ Cl ₂ (50 mL) and the reaction was cooled in an ice water bath. Then CH ₃ SO ₂ Cl (5.5 g, 47.8 mmol) was added dropwise and the mixture was stirred in an ice water bath for 10 minutes. The resulting yellow mixture was diluted with saturated aqueous NaHC0 ₃ solution and extracted several times with CH ₂ Cl ₂ until no product remained in the aqueous layer by TLC. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in EtOH (85 mL) and heated to reflux for 16 h. The reaction mixture was cooled to room temperature and transferred to a Parr bottle and treated with 10% Pd / C catalyst (1.25 g). The bottle was placed under hydrogen (53 psi) atmosphere for 16 hours. The reaction mixture was filtered through celite and fresh catalyst (10% Pd / C, 1.25 g) was added. Hydrolysis continued overnight. The process was repeated three more times until hydrogenolysis was complete. The final mixture was filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with CHCl ₃ -MeOH-NH ₄ 0H (90: 9.5: 0.5) gave intermediate 7 as a white solid (yield 46%): ¹ H NMR (CDCl ₃ ) δ5.6-5.5, 3.8-3.7, 3.3 -3.2, 2.8-2.7, 2.0-1.8, 1.7-1.5, 1.5.

Step H. Preparation of exo-3-amino-1-azabicyclo [2.2.1] heptane bis (hydro para-toluenesulfonate).

Para-toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) was added Intermediate 7 (770 mg, 3.63 mmol) in EtOH (50 mL) to the stirred solution. The reaction mixture was heated to reflux for 10 hours and then cooled to room temperature. The precipitates were collected by vacuum filtration and washed with cold EtOH (as racemic mixture) to give exo- [2.2.1] -3-amine as a white solid (yield 84%): ¹ H NMR (CD ₃ OD) δ 7.7, 7.3, 3.9-3.7, 3.7-3.3, 3.2, 2.4, 2. 3-2.2, 1.9-1.8. Corresponding amines can be obtained using split intermediate 6 from which exo- (4R)-[2.2.1] -3-amine and exo- (4S)-[2.2.1] -3-amine are obtained.

Synthesis of endo-3-amino-1-azabicyclo [2.2.1] heptane as bis (hydro para-toluenesulfonate) salt:

Step I. Preparation of ethyl 5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (intermediate 10).

Anhydrous EtOH (92.0 mL, 1.58 mol) was added to a mechanically stirred suspension of potassium ethoxylate (33.2 g, 395 mmol) in anhydrous toluene (0.470 L). When the mixture was homogeneous, 2-pyrrolidinone (33.6 g, 395 mmol) was added and then a solution of diethyl oxalate in toluene (98 mL) was added via an addition funnel. After the addition was complete, toluene (118 mL) and EtOH (78 mL) were added sequentially. The mixture was heated to reflux for 18 hours. The mixture was cooled to rt and aqueous HCl (150 mL of 6.0 M solution) was added. The mixture was mechanically stirred for 15 minutes. The aqueous layer was extracted with CH ₂ Cl ₂ , the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give a yellow residue. The residue was recrystallized in EtOAc to afford intermediate 10 as a yellow solid (yield 38%): ¹ H NMR (CDCl ₃ ) δ 11.4, 7.4, 4.3, 3.4, 2.6, 1.3.

Step J. Preparation of ethyl cis-3-hydroxy-2-oxopiperidine-4-carboxylate (intermediate 11).

A mixture of intermediate 10 (15 g, 81 mmol) and 5% rhodium on carbon (2.0 g) in glacial acetic acid was placed under hydrogen (52 psi) atmosphere. The mixture was shaken for 72 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo to yield intermediate 11 as a white solid (98% yield): ¹ H NMR (CDCl ₃ ) δ 6.3, 4.2, 4.0-3.8, 3.4, 3.3- 3.2, 2.2, 1.3.

Step K. Preparation of cis-4- (hydroxymethyl) piperidin-3-ol (intermediate 12).

Intermediate 11 (3.7 g, 19.9 mmol) as a solid was added in small portions to a stirred solution of LiAlH ₄ in THF (80 mL of 1.0 M solution) in an ice water bath. The mixture was warmed to rt and the reaction was then heated to reflux for 48 h. After cooling the mixture in an ice-water bath, water (3.0 mL, 170 mmol) was added dropwise, followed by addition of NaOH (3.0 mL of 15% (w / v) solution) and water (9.0 mL, 500 mmol) sequentially. Excess K ₂ CO ₃ was added and the mixture was vigorously stirred for 15 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give intermediate 12 as a yellow powder (yield 70%): ¹ H NMR (DMSO-d ₆ ) δ4.3, 4.1, 3.7, 3.5-3.2, 2.9-2.7 , 2.5-2.3, 1.5, 1.3.

Step L. Preparation of benzyl cis-3-hydroxy-4- (hydroxymethyl) piperidine-1-carboxylate (Intermediate 13).

N- (benzyloxy carbonyloxy) succinimide (3.04 g, 12.2 mmol) was added to a stirred solution of intermediate 12 (1.6 g, 12.2 mmol) in saturated aqueous NaHCO ₃ (15 mL) at room temperature. The mixture was stirred at rt for 18 h. The organic and aqueous layers were separated. The aqueous layer was extracted with ether (3 ×). The combined organic layers were dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo to yield intermediate 13 as a yellow oil (yield 99%): ¹ H NMR (CDCl ₃ ) δ 7.4-7.3, 5.2, 4.3, 4.1, 3.8-3.7, 3.0-2.8, 2.1, 1.9-1.7, 1.4.

Step M. Preparation of benzyl cis-3-hydroxy-4-[(4-methylphenyl) sulfonyl oxymethyl] piperidine-1-carboxylate (intermediate 14).

Para-toluenesulfonyl chloride (1.0 g, 5.3 mmol) was added to a stirred solution of intermediate 13 (3.6 g, 5.3 mmol) in pyridine (10 mL) in a -15 ° C bath. The mixture was stirred for 4 hours, then HCl (4.5 mL of 6.0 M solution) was added. CH ₂ Cl ₂ (5 mL) was added. The organic and aqueous layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to yield intermediate 14 as colorless oil (yield 78%): ¹ H NMR (CDCl ₃ ) δ 7.8, 7.4-7.2, 5.1 , 4.3-4.2, 4.1, 3.9-3.8, 2.9-2.7, 2.4, 1.9, 1.6-1.3.

Step N. Preparation of exo-1-azabicyclo [2.2.1] heptan-3-ol (intermediate 15).

A mixture of intermediate 14 (3.6 g, 8.6 mmol) and 10% Pd / C catalyst (500 mg) in EtOH (50 mL) was placed under hydrogen atmosphere. The mixture was shaken for 16 hours. The mixture was filtered through celite. Solid NaHCO ₃ (1.1 g, 13 mmol) was added to the filtrate and the mixture was heated to 50 ° C. in an oil bath for 5 hours. The solvent was removed in vacuo. The residue was dissolved in saturated aqueous K ₂ CO ₃ solution. After continuously extracting the aqueous layer using a liquid-liquid extraction device (for 18 hours), the organic layer was dried over anhydrous K ₂ CO ₃ and the solvent was removed in vacuo to yield intermediate 15 as a white solid (91% yield). : ¹ H NMR (CDCl ₃ ) δ 3.8, 3.0-2.8, 2.6-2.5, 2.4-2.3, 1.7, 1.1.

Step O. Preparation of Endo-3-azido-1-azabicyclo [2.2.1] heptane (Intermediate 16).

Hydra in toluene (2 M solution0 15 mL) in a mixture of intermediate 15 (1.0 g, 8.9 mmol) and triphenyl phosphine (3.0 g, 11.5 mmol) in toluene-THF (50 mL, 3: 2) in an ice bath. The crude acid solution and a solution of diethyl azadicarboxylate (1.8 mL, 11.5 mmol) in toluene (20 mL) were added sequentially. The mixture was allowed to warm to rt and stirred for 18 h. The mixture was extracted with 1.OM HCl aqueous solution. The aqueous layer was extracted with EtOAc and the combined organic layers were discarded. The pH of the aqueous layer was adjusted to 9 with 50% NaOH aqueous solution. The aqueous layer was extracted with CH ₂ Cl ₂ (3 ×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel. Elution with CHCl ₃ -MeOH-NH ₄ OH (92: 7: 1) gave intermediate 16 as a colorless oil (yield 41%): ¹ H NMR (CDCl ₃ ) δ4.1, 3.2, 2.8, 2.7-2.5 , 2.2, 1.9, 1.5.

Step P. Preparation of endo-3-amino-1-azabicyclo [2.2.1] heptane bis (hydro para-toluenesulfonate).

A mixture of intermediate 16 (250 mg, 1.8 mmol) and 10% Pd / C catalyst (12 mg) in EtOH (10 mL) was placed under hydrogen (15 psi) atmosphere. The mixture was stirred at rt for 1 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was dissolved in EtOH (10 mL) and para-toluenesulfonic acid monohydrate (690 mg, 3.7 mmol) was added. The mixture was stirred for 30 minutes and the precipitate was filtered off. The precipitate was washed sequentially with cold EtOH and ether. The precipitate was dried in vacuo to give endo- [2.2.1] -3-amine as a white solid (yield 85%): ¹ H NMR (CD ₃ OD) δ 7.7, 7.3, 4.2, 3.9, 3.6-3.4 , 3.3-3.2, 2.4, 2.3, 2.1.

Preparation of 3.2.1-amines :

Exo- and endo-1-azabicyclo [3.2.1] octane-3-amines are described in Lewin, A. H., et al. Med. Chem., 988-995 (1998)] according to the general procedure discussed in 1-azabicyclic [3.2.1] octan-3-one (Thill, BP, Aaron, HS, J. Org.Chem., 4376-4380 (1968)].

Exo-1-azabicyclo [3.2.1] octane-3-amine dihydrochloride (exo- [3.2.1] -amine):

A mixture of 1-azabicyclo [3.2.1] octan-3-one hydrochloride (2.80 g, 17.3 mmol), ethanol (25 mL) and hydroxylamine hydrochloride (1.56 g, 22.4 mmol) was dissolved in sodium acetate trihydrate ( 7.07 g, 51.2 mmol). The mixture was stirred for 3 hours and evaporated in vacuo. The residue was diluted with CH ₂ Cl ₂ , treated with charcoal, filtered and evaporated. The resulting material was dissolved in 1-propanol (45 mL) and heated in a 100 ° C. oil bath. The solution was treated with sodium metal (divided 6.4 g). Continue heating for 3 hours and cool the mixture to room temperature. Water was added carefully, the organic layer was extracted, dried (MgSO ₄ ), filtered, acidified with MeOH / HCl (g) and evaporated. 2-propanol was added and the resulting solid was dried in filtration and in vacuo to give exo- [3.2.1] -amine in 49% yield. MS (ESI) (M + H) ⁺ m / z = 127 for C ₇ H ₁₄ N _2. (HCl) ₂ .

Endo-1-azabicyclo [3.2.1] octan-3-amine dihydrochloride (endo- [3.2.1] -amine):

A mixture of 1-azabicyclo [3.2.1] octan-3-one hydrochloride (2.80 g, 17.3 mmol), ethanol (25 mL) and hydroxylamine hydrochloride (1.56 g, 22.4 mmol) was dissolved in sodium acetate trihydrate ( 7.07 g, 51.2 mmol). The mixture was stirred for 3 hours and evaporated in vacuo. The residue was diluted with CH ₂ Cl ₂ , treated with charcoal, filtered and evaporated. The resulting oxime (3.1 mmol) was treated with acetic acid (30 mL) and hydrogenated at 50 psi with PtO ₂ (50 mg) for 12 h. The mixture was then filtered and evaporated. The residue was dissolved in a minimum amount of water (6 mL) and the pH was adjusted to greater than 12 with solid NaOH. The mixture was then extracted with ethyl acetate (4 × 25 mL), dried over MgSO ₄ , filtered, treated with ethereal HCl and evaporated to give endo- [3.2.1] -amine.

1-azabicyclo [3.2.1] octan-3-amine:

Preparation of 3R, 5R- [3.2.1] -amines:

Such amines may be prepared according to the following method:

(3S) -1-[(S) -1-Phenyl] -5-oxo-3-pyrrolidine-carboxylic acid:

Process of literature [Nielsen et al. J. Med. Chem 1990, 70-77], a mixture of itaconic acid (123.17 g, 946.7 mmol) and (S)-(-)-α-methyl benzylamine (122.0 mL, 946.4 mmol) in a 160 ° C. oil bath for 4 hours. Heated (pure) for a while. While cooling, MeOH (˜200 mL) was added and the resulting solid collected by filtration. The solid was treated with EtOH (˜700 mL) and warmed using a steam bath until the solvent remained at about 450 mL. Cool to room temperature, combine the solids and dry to give 83.2 g as crystalline solids: [α] ²⁵ _D = -80 (c 0.97, DMSO). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.66, 7.20-7.40, 5.23, 3.40-3.55, 3.10-3.25, 2.40-2.65, 1.45; MS (EI) m / z 233 (M ⁺ ).

(3S) -1-[(S) -1-phenethyl] -3- (hydroxymethyl) pyrrolidine:

Suspension (3S) -1 of _{Et 2 O (200 mL) -} [(S) -1- phenethyl] -5-oxo-3-pyrrolidine-carboxylic acid (82.30 g, 352.8 mmol) with Et ₂ O To a slurry of LiAlH ₄ (17.41 g, 458.6 mmol) in (700 mL) was added in small portions. Reflux of the mixture was started during the addition. The addition funnel containing the suspension is rinsed with Et ₂ 0 (2 x 50 mL) and the mixture is heated in a 50 ° C. oil bath for an additional 2 hours, first cooled to room temperature and then further cooled with an ice bath. It was. The mixture was carefully treated with H ₂ 0 (62 mL). The resulting precipitate was filtered off, rinsed with Et ₂ 0 and discarded. The filtrate was concentrated to give a yellow oil. When EtOAc was added to the oil, a solid formed. Hexane was then added, the mixture was filtered and the solid dried to give 43.3 g: [a] ²⁵ _D = -71 (c 0.94, CHCl ₃ ); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20-7.45, 3.60-3.70, 3.40-3.60, 3.19, 3.05-3.15, 2.35-2.55, 2.25-2.35, 1.95-2.10, 1.75-1.90, 1.42; HRMS (FAB) theory for C ₁₃ H ₁₉ NO (MH ⁺ ) 206.1545, found 206.1532.

(3R) -1-[(S) -1-phenethyl] -3- (cyanomethyl) pyrrolidine:

A solution of (3S) -1-[(S) -1-phenethyl] -3- (hydroxymethyl) pyrrolidine (42.75 g, 208.23 mmol) in chloroform (350 mL) was heated to reflux under N ₂ atmosphere. . The solution was treated dropwise over 45 minutes with a solution of thionyl chloride (41.8 mL, 573 mmol) in chloroform (40 mL). The mixture was stirred for an additional 30 minutes, cooled and concentrated. The residue was diluted with H ₂ 0 (˜200 mL) and 1 N NaOH was added until the pH was about 8 (pH paper). A small portion (~ 50 mL) of saturated NaHC0 ₃ is added and the basic mixture is extracted with EtOAc (3 × 400 mL), washed with brine, dried over MgSO ₄ , filtered and concentrated to give 46.51 g of (3S ) -1-[(S) -1-phenethyl] -3- (chloromethyl) pyrrolidine was obtained: MS (ESI +) m / z 224.2 (MH ⁺ ). Chloride (46.35 g, 208.0 mmol) was transferred to the flask, DMSO (200 mL) was added, and the solution was treated with NaCN (17.84 g, 363.9 mmol). The mixture was heated and cooled overnight in a 100 ° C. oil bath under N ₂ . The brown mixture was poured into H ₂ 0 (300 mL) and extracted with EtOAc (divide 1000 mL). The combined organic layers were washed with H ₂ 0 (6 × 50 mL) and brine (˜100 mL), dried (MgSO ₄ ), filtered and concentrated to give 40.61 g of oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20-7.40, 3.26, 2.70-2.85, 2.40-2.60, 2.27, 2.10-2.20, 1.50-1.70, 1.41; MS (ESI +) m / z 215.2 (M + H ⁺ ).

(3R) -Methyl 1-[(S) -1-phenylethyl] pyrrolidine-3-acetate:

Acetyl chloride (270 mL, 3.8 mol) was carefully added to the flask containing chilled (0 ° C.) methanol (1100 mL). After the addition was complete, the acidic solution was stirred for 45 min (0 ° C.), then (3R) -1-[(S) -1-phenethyl] -3- (cyanomethyl in methanol (200 mL) Pyrrolidine (40.50 g, 189.0 mmol) was added. The ice bath was removed and the mixture was stirred at rt for 100 h. The resulting suspension was concentrated. Water (˜600 mL) was added and the mixture was stirred for 45 min, then pH was adjusted (prepared to basic) by addition of ₃ to 700 mL of saturated aqueous NaHC0 solution. The mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered over celite and concentrated to give 36.86 g as oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20-7.40, 3.69, 3.30- 3.40, 2.85-2.95, 2.40-2.70, 2.00-2.20, 1.10-1.65; MS (ESI +) m / z 248.2 (M + H ⁺ ).

(5R) -1-Azabicyclo [3.2.1] octan-3-one hydrochloride:

A solution of (3R) -methyl 1-[(S) -1-phenylethyl] pyrrolidine-3-acetate (25.72 g, 104.0 mmol) in THF (265 mL) was cooled in a CO ₂ / acetone bath under N ₂ It was. ICH ₂ Cl (22.7 mL, 312.0 mmol) was added and the mixture was stirred for 30 minutes. A solution of 2.0 M lithium diisopropylamide (heptane / THF / ethylbenzene, 156 mL, 312 mmol) was added slowly over 30 minutes. The internal temperature reached a maximum of -40 ° C during the addition. After 1 h saturated NH ₄ Cl (100 mL) was added and the mixture was allowed to warm to room temperature. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated. The resulting foam was chromatographed (Si0 ₂ 300 g, CHCl ₃ -MeOH-NH ₄ 0H (89: 10: 1), then CHCl ₃ -MeOH (3: 1)). The product fractions were combined and concentrated to give (5R) -3-oxo-1-[(lS) -1-phenylethyl] -1-azoniabicyclo [3.2.1] octane chloride (10.12 g) as a foam (MS (ESI +) m / z 230.1 (M + H ⁺ )). The foam (10.1 g, 38 mmol) was dissolved in MeOH (500 mL), 10% Pd (C) (3.0 g) was added and the mixture was hydrogenated overnight (45 psi). The mixture was filtered and re-run under reducing conditions (9.1 g, 10% Pd / C, 50 psi). After 5 hours, TLC showed (5R) -3-oxo-1-[(1S) -1-phenylethyl] -1-azoniabicyclo [3.2.1] octane chloride to be consumed. The mixture was filtered, concentrated and triturated (minimum iPrOH) to give 3.73 g of two crops as a solid: [α] ²⁵ _D = 33 (c 0.97, DMSO); HRMS (FAB) theory for C ₇ H ₁₁ NO (M + H ⁺ ) 126.0919, found 126.0937.

(3R, 5R) -1-Azabicyclo [3.2.1] octane-3-amine dihydrochloride:

Flask containing (5R) -1-azabicyclo [3.2.1] octan-3-one hydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g, 29.4 mmol) and ethanol (130 mL) To this was added sodium acetate trihydrate (9.23 g, 67.8 mmol). The mixture was stirred for 3 hours, filtered and concentrated. The resulting white solid was dissolved in n-propanol (100 mL) and sodium (˜13.6 g, 618 mmol) was added in portions of 20-25 times. Reflux of the reaction started spontaneously and the reaction was heated in an oil bath (100 ° C.). The addition was complete for about 20 minutes and the mixture solidified after about 40 minutes. The oil bath was removed and n-propanol (2 x 25 mL) was added to dissolve the remaining sodium metal. The mixture was quenched carefully by dropwise addition of H ₂ 0 (100 mL). Saturated aqueous NaCl solution (20 mL) was added and the layers were separated. The organic layer was dried (MgSO ₄ ), filtered, treated with freshly prepared MeOH / HCl and concentrated. The resulting solid was triturated with 30 mL of EtOH, filtered and dried in vacuo to yield 3.51 g as a white solid: [α] ²⁵ _D = -3 (c 0.97, DMSO); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.60-3.80, 2.95-3.10, 2.65-2.75, 1.90-2.15, 1.70-1.90; HRMS (FAB) theory for C ₇ H ₁₄ N ₂ (M + H ⁺ ) 127.1235, found 127.1235.

Preparation of 1-azabicyclo [3.2.2] nonan-3-amine bis (4-methylbenzenesulfonate) ([3.2.2] -amine)

Preparation of tert-butyl 4- (2-oxopropylidine) piperidine-1-carboxylate (intermediate 101):

Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) was washed with pentane (3 ×) and suspended in anhydrous THF (40 mL). After cooling the solution to 0 ° C., diethyl (2-oxopropyl) phosphonate (9.75 g, 50.2 mmol) was added dropwise. After the addition was complete, the solution was allowed to warm to room temperature and stirred for 30 minutes. tert-Butyl 4-oxo-1-piperidinecarboxylate (5.0 g, 25.1 mmol) was added portionwise over 10 minutes and then stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added and then diluted with ether. The organic layer was extracted with water. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated to give a yellow oil. The crude product was purified by flash chromatography on silica gel. Elution with hexane-ether (60:40) gave 4.5 g (75%) of intermediate 101 as a white solid: ¹ H NMR (CDCl ₃ ) δ 6.2, 3.5, 3.4, 2.9, 2.3, 2.2, 1.5.

Preparation of tert-butyl 4- (2-oxopropyl) piperidine-1-carboxylate (intermediate 102):

A mixture of intermediate 101 (4.5 g, 19 mmol) and 10% palladium on activated carbon (450 mg) in EtOH (150 mL) was placed in a Parr bottle and hydrogenated to 50 psi for 5 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give 4.3 g (94%) of intermediate 102 as a clear oil: ¹ H NMR (CDCl ₃ ) δ4.1, 2.8, 2.4, 2.2, 2.0, 1.7 , 1.5, 1.1.

Preparation of tert-butyl 4- (3-bromo-2-oxopropyl) piperidine-1-carboxylate (intermediate 103):

Chlorotrimethylsilane (11.0 mL, 86.4 mmol) was added dropwise to a stirred solution of lithium hexamethyldisilylamide in THF (20.0 mL, 1.0 M) in a -78 ° C bath. The mixture was stirred at -78 ° C for 20 minutes, then intermediate 102 (3.21 g, 13.3 mmol) in a solution of THF (50 mL) was added dropwise. After the addition was complete, the mixture was stirred at −78 ° C. for 30 minutes. The mixture was warmed to 0 ° C. in an ice water bath and phenyltrimethylammonium tribromide (5.25 g, 14.0 mmol) was added. The mixture was stirred for 30 minutes in an ice water bath, then water and ether were added. The aqueous layer was washed with ether and the combined organic layers were washed with saturated aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash chromatography on silica gel. Elution with hexane-ether (60:40) gave 2.2 g (52%) of intermediate 103 as a yellow oil: ¹ H NMR (CDCl ₃ ) δ4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1-2.0 , 1.7, 1.5, 1.2-1.1.2.

Preparation of 1-bromo-3-piperidin-4-ylacetone trifluoroacetate (intermediate 104):

Trifluoroacetic acid (10 mL, 130 mmol) was added to a stirred solution of intermediate 103 (2.2 g, 6.9 mmol) in CH ₂ Cl ₂ (30 mL) in an ice water bath. The mixture was stirred at 0 ° C for 30 minutes. The volatiles were removed in vacuo to yield 2.0 g (87%) of intermediate 104 as a yellow residue: MS (ESI) [M + H] m / e 220 for C ₈ H ₁₅ BrNO.

Preparation of 1-azabicyclo [3.2.2] nonan-3-one (intermediate 105):

To a stirred solution of DIEA (13 mL) in acetonitrile (680 mL) at reflux was added intermediate 104 (2.0 g, 6.0 mmol) in acetonitrile (125 mL) over 4 hours via a syringe pump. The mixture was stored at reflux overnight. The mixture was concentrated in vacuo and the remaining residue was partitioned between saturated aqueous K ₂ CO ₃ solution and CHCl ₃ -MeOH (90:10). The aqueous layer was extracted with CHCl ₃ -MeOH (90:10), and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel. Elution with CHCl ₃ -MeOH-NH ₄ 0H (95: 4.5: 0.5) gave 600 mg (72%) of intermediate 105 as a clear solid: ¹ H NMR (CDCl ₃ ) δ 3.7, 3.3-3.2, 3.1-3.0 , 2.7, 2.3, 2.0-1.8.

To a stirred mixture of intermediate 105 (330 mg, 2.4 mmol) and sodium acetate trihydrate (670 mg, 4.8 mmol) in EtOH (6.0 mL) was added hydroxylamine-hydrochloride (200 mg, 2.8 mmol). The mixture was stirred at rt for 10 h. The mixture was filtered and the filtrate was concentrated in vacuo to yield a yellow solid. To a solution of the solid (350 mg, 2.3 mmol) in n-propanol (30 mL) at reflux temperature was added sodium metal (2.0 g, 87 mmol) in small portions over 30 minutes. Heating was continued at reflux for 2 hours. The solution was cooled to room temperature and brine was added. The mixture was extracted with n-propanol and the combined organic layers were concentrated in vacuo. The residue was dissolved in CHCl ₃ and the residual solid was filtered off. The filtrate was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a clear solid. To a stirred solution of the solid (320 mg, 2.3 mmol) in EtOH (4 mL) was added p-toluenesulfonic acid monohydrate (875 mg, 4.6 mmol). The solution was warmed in water bath to 45 ° C. for 30 min and the solvent was concentrated to give 710 mg (62%) of [3.2.2] -amine as a white solid: ¹ H NMR (CD ₃ OD) δ7.7, 7.3, 4.1-3.9, 3.6-3.4, 2.6-2.5, 2.4, 2.2-2.1, 2.1-2.0, 1.9.

Segmentation of Stereoisomers:

The amines can be coupled to form suitable amides or thioamides as racemic mixtures. The racemic mixture is then partitioned by chromatography, a technique well known in the art using chiral columns or chiral HPLC, to provide the essential split enantiomers 3 (R) and 3 (S) of the amide or thioamide. can do.

The following examples are provided by way of illustration and are not intended to limit the scope of the present invention but merely to provide examples and named compounds. In addition, the salts prepared in the examples are illustrative only and are not intended to limit the present invention. Any pharmaceutically acceptable salt can be prepared by one skilled in the art. In addition, the names of specific stereoisomers are for exemplification, and the absence of names of specific stereoisomers is for simplification, and the nomenclature is not intended to limit the scope of the present invention in any way. The present invention includes the following examples as pure stereoisomeric forms of all optically active centers or as racemic mixtures.

The examples presented can also be carried out using the specific amines indicated in the examples. However, any of the amines described do not cause significant changes or cannot be used to start with an appropriate amine. Accordingly, stereoisomeric specificity of the resulting compounds is not shown and will not be described. However, the scope of the present invention includes racemic mixtures as well as other stereoisomers as used herein.

Coupling of Amine and Essential Acids:

Example 1 (i) : Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide fumarate :

2-chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO ₃ (19.5 g, 0.232 mole, 1.5 equiv) and 150 mL of water were placed in the flask. The flask was placed in an oil bath at 90 ° C. and after 5 minutes 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5 equiv) was added in six unequal amounts, i.e. 12 mL, 3 x 8 There was a time difference of 90 minutes with mL, then 2.2 mL, then the reaction was stirred at 90 ° C. for 15 h and finally 2.3 mL was added. The reaction was stirred for additional 4 h at 90 ° C. and then the flask was placed in an ice bath to cool. The pH of the reaction was adjusted to 1 with 6N HCl. The reaction was stirred in an ice bath for 1.5 hours to form an unwanted solid. This undesired solid was removed by filtration and the filtrate was extracted seven times with EtOAc. The combined organic extracts are concentrated in vacuo, toluene is added to the flask and removed in vacuo to give azeotropic water, then CH ₂ Cl ₂ is added and removed in vacuo to be sufficiently pure for the subsequent reaction. Chloro-6- (hydroxymethyl) -3-pyridinol ( C1 ) was obtained as a light yellow solid (yield 81%). MS (EI) for C ₆ H ₆ ClN0 ₂ , m / z: 159 (M) ⁺ .

C1 (11.6 g, 72.7 mmol) and NaHCO ₃ (18.3 g, 218 mmol) were added to 200 mL of H ₂ O. The mixture was stirred until homogeneous, the flask was placed in an ice bath, iodine (19.4 g, 76.3 mmol) was added and the reaction was stirred at rt over the weekend. The pH of the mixture was adjusted to 3 with 2N NaHS0 ₄ and the mixture was extracted with 4 × 50 mL of EtOAc. The combined organic layers were dried over MgSO ₄ , filtered, and the filtrate was concentrated in vacuo to give a yellow solid. The crude solid was washed with EtOAc to afford 2-chloro-6- (hydroxymethyl) -4-iodo-3-pyridinol ( C2 ) as off-white solid (yield 62%) and the filtrate in small volume. Concentrate and chromatograph with 250 g of silica gel (230-400 mesh) eluting with EtOAc / CH ₂ Cl ₂ / hexanes / acetic acid at 2.5: 4.5: 4: 0.1 to give additional pure C2 (yield 12%). MS (EI) for C ₆ H ₅ ClIN0 ₂ , m / z: 285 (M) ⁺ .

C2 (13.9 g, 48.6 mmol) trimethylsilylacetylene (9.6 mL, 68 mmol), bis (triphenylphosphine) palladium dichloride (1.02 g, 1.46 mmol) in 80 mL / THF 40 mL CHCl ₃ under N ₂ and Combined with copper iodide (139 mg, 0.73 mmol). TEA (21 mL, 151 mmol) was added and the reaction was stirred at rt for 3 h and diluted with 200 mL of CHCl ₃ . The mixture was washed with 2 x 150 mL of 5% HCl and the combined aqueous layers were extracted with 2 x 50 mL of CHCl ₃ . The combined organic layers were washed with 100 mL of 50% saturated NaCl, dried over MgSO ₄ and concentrated in vacuo to give an amber oil. The crude material was chromatographed with 350 g of silica gel (230-400 mesh) eluting with 35% EtOAc / hexanes to 2-chloro-6- (hydroxymethyl) -4-[(trimethylsilyl) ethynyl] -3-pyridine Dinol ( C3 ) was obtained as a gold solid (yield 92%). MS (EI) for C ₁₁ H ₁₄ ClNO ₂ Si, m / z: 255 (M) ⁺ .

C3 (7.9 g, 31.2 mmol) and copper iodide (297 mg, 1.6 mmol) in 60 mL EtOH 60 mL / TEA were added to the flask. The reaction was placed in an oil bath at 70 ° C. for 3.5 h, cooled to rt and concentrated in vacuo. The residue was partitioned between 100 mL of 5% HCl and CH ₂ Cl ₂ (4 × 50 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give 6.5 g of an amber crude solid. The crude material was chromatographed with 300 g of silica gel (230-400 mesh) eluting with 30-40% EtOAc / hexanes. Two fractions of the two different compounds of interest were identified by TLC / UV. The two compounds were eluted separately. The early-eluting pools of fractions were combined and concentrated to afford [7-chloro-2- (trimethylsilyl) furo [2,3-c] pyridin-5-yl] methanol ( C5 ) as a white solid (yield 46%). . The late-eluting pools of fractions were combined and concentrated to give (7-chlorofuro [2,3-c] pyridin-5-yl) methanol ( C4 ) as a white solid (yield 27%). MS (EI) for C ₈ H ₆ ClN0 ₂ according to C4, m / z: 183 ( M) +. HRMS (FAB) theory for C ₁₁ H ₁₄ ClNO ₂ Si for C 5 m / z: 255.0482, found 255.0481.

C5 (1.05 g, 4.1 mmol) and 10% Pd / C catalyst (1.05 g) were placed in 20 mL of anhydrous EtOH. Cyclohexene (4 mL, 40.1 mmol) was added and the reaction was refluxed for 2.5 h and then filtered through celite. The filter cake was washed with 1: 1 EtOH / CH ₂ Cl ₂ and the filtrate was concentrated to give a pale yellow solid. The residue was partitioned between 40 mL of saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (4 × 20 mL). The combined organic layers were dried over MgSO ₄ , filtered and then concentrated in vacuo to give a pale oil (1.04 g). The pale oil was chromatographed with 50 g of silica gel (230-400 mesh) eluting with 50-70% EtOAc / hexanes to 5-hydroxymethyl-2-trimethylsilyl-furo [2,3-c] pyridine ( C14 ) Was obtained as a white solid (yield 90%): MS (EI) for C ₁₁ H ₁₅ NO ₂ Si, m / z: 221 (M) ⁺ .

C14 (770 mg, 3.48 mmol) was dissolved in 10 mL of MeOH. 2N NaOH (3 mL, 6 mmol) was added and the reaction stirred at rt for 1.5 h. The solution was concentrated in vacuo to give a residue. Water (20 mL) was added to the residue and extracted with CH ₂ Cl ₂ 4 × 10 mL. The combined organic layers were dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo to give furo [2,3-c] pyridin-5-yl methanol ( C16 ) as a white solid (90% yield). Analytical Theory for C ₈ H ₇ NO ₂ : C, 64.42; H, 4.73; N, 9.39. Found: C, 64.60; H, 4.56; N, 9.44.

Under N ₂ , oxalyl chloride (685 μl, 7.8 mmol) was dissolved in 30 mL CH ₂ Cl ₂ in a dried flask. The flask was placed in a dry ice / acetone bath, DMSO (1.11 mL, 15.6 mmol) in 5 mL of CH ₂ Cl ₂ was added dropwise and the mixture was stirred for 20 minutes. C16 (1.0 g, 6.7 mmol) in 10 mL of CH ₂ Cl ₂ was added and the reaction was stirred at −78 ° C. for 30 minutes. TEA (4.7 mL, 33.5 mmol) was added and the reaction was allowed to warm to rt, stirred for 1 h and washed with 25 mL of saturated NaHCO ₃ . The organic layer was dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo to afford an orange solid. The crude was chromatographed with 50 g of silica gel (230-400 mesh) eluting with 33% EtOAc / hexanes to give furo [2,3-c] pyridine-5-carbaldehyde ( C17 ) as a white solid (yield 86%). Obtained as MS (EI) for C ₈ H ₅ NO ₂ , m / z: 147 (M) ⁺ .

C17 (850 mg, 5.8 mmol) was dissolved in 10 mL of DMSO. KH ₂ PO ₄ (221 mg, 1.6 mmol) in H ₂ 0 3 mL is added, followed by NaClO ₂ (920 mg, 8.2 mmol) in H ₂ 0 7 mL and the reaction is stirred at rt for 3 h. It was. The reaction was diluted with 25 mL of water, the pH was adjusted to 10 with 2N NaOH and the mixture was extracted with 3 x 20 mL of ether. The combined ether layers were discarded. The pH of the aqueous layer was adjusted to 3.5 with 10% aqueous HCl and extracted with 13 × 10 mL of 10% MeOH / CH ₂ Cl ₂ . The MeOH / CH ₂ Cl ₂ organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to give a pale oil. The residual DMSO was removed under steam of N ₂ at room temperature to give a white paste. The paste was dissolved in MeOH and concentrated to dryness. The white solid was washed with ether and dried to give crude furo [2,3-c] pyridine-5-carboxylic acid ( C18 ) (yield 94%). MS (ESI) for C ₈ H ₅ NO ₃ , 162.8 (MH) ⁻ .

Step 1a. Preparation of Carboxamides:

DIEA (956 μl, 5.49 mmol) in a stirred solution of furo [2,3-c] pyridine-5-carboxylic acid ( C18 ) (294 mg, 1.80 mmol) in dry THF-DMF (12 mL, 5: 1). Was added followed by exo- (4S)-[2.2.1] -3-amine (747 mg, 1.64 mmol). The solution was cooled in an ice bath and HATU (684 mg, 1.80 mmol) was added. The solution was allowed to warm to rt and stirred for 16 h. The solvent was removed in vacuo and the remaining residue was partitioned between saturated aqueous K ₂ CO ₃ aqueous solution and 9: 1 CHCl ₃ -MeOH. The aqueous layer was extracted with 9: 1 CHCl ₃ -MeOH, the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to afford the desired carboxamide as a pale yellow solid (420 mg, 100%). Obtained as MS (ESI) for C ₁₄ H ₁₆ N ₃ 0 ₂ m / e 258 (M + H).

Step 1b. Preparation of Fumarate Salts.

To a stirred solution of the product from step 1a (200 mg, 0.78 mmol) in acetone (5 mL) was added a hot solution of fumaric acid (90 mg, 0.78 mmol) in IPA (2 mL). The mixture was stirred in a 50 ° C. water bath for 30 minutes. The solvent was removed in vacuo and the residue was dissolved in acetone (5 mL). The mixture was stirred overnight at room temperature. Solid precipitate was collected by filtration and washed with acetone. The solid was dried in vacuo overnight to give 156 mg (54%) of Example 1 (i) as a white solid: ¹ H NMR (CD ₃ 0D) δ 8.9, 8.5, 8.1, 7.1, 6.7, 4.3, 3.7, 3.6 , 3.4, 3.3, 3.2, 3.1, 2.2,1.9.

Example 1 (ib) : Exo-4 (R) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo using exo- (4R)-[2.2.1] -3-amine [2,3-c] pyridine-5-carboxamide: ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.9, 8.5, 8.1, 7.1, 6.7, 4.3, 3.7, 3.6, 3.4, 3.3, 3.2, 3.1, 2.2, 1.9.

Example 1 (ic) : exo- (racemic) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3 using exo- [2.2.1] -3-amine -c] pyridine-5-carboxamide.

Example 1 (id) : (+)-N- [endo-1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-5-carboxamide and

Example 1 (ie) : (-)-N- [endo-1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-5-carboxamide:

To a stirred solution of furo [2,3-c] pyridine-5-carboxylic acid (400 mg, 0.877 mmol) in anhydrous DMF (10 mL), DIEA (626 μl, 3.59 mmol) and endo- [2.2.1]- 3-amine (175 mg, 0.877 mmol) was added. The mixture was cooled to 0 ° C. in an ice bath and HATU (333 mg, 0.877 mmol) was added in one portion. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous K ₂ CO ₃ solution and CHCl ₃ . The aqueous layer was extracted with CHCl ₃ (2 ×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 230 mg of solid. The racemic mixture was partitioned via chromatography using a Chiralcel OJ column. The amide was converted to its fumarate salt form as described in step 1b. Example 1-d is obtained from the (+)-enantiomer ([α] ²⁵ _D 31 (c 0.28, MeOH)) and the (-)-enantiomer ([α] ²⁵ _D -31 (c 0.30, MeOH) Example 1-e was obtained. For Examples 1-d: ¹ H NMR (400 MHz, CD ₃ 0D) δ 8.94, 8.46, 8.14, 7.13, 6.71, 4.75-4.70, 3.86-3.79, 3.48-3.42, 3.28-3.21, 2.21-2.03 .

Example 1 (if): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide: this example Can be prepared according to the coupling procedure discussed herein.

Example 1 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide: this example Can be prepared according to the coupling procedure discussed herein.

Example 1 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide: This example is a couple discussed herein. It can be prepared according to the ring process.

Example 1 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide: This example is a couple discussed herein. It can be prepared according to the ring process.

Example 1 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide: from coupling The yield of was 70%. HRMS (FAB) theory for C ₁₅ H ₁₇ N ₃ 0 ₂ (MH ⁺ ) 272.1399. Found 272.1413.

Example 1 (vi): N- (1-azabicyclo [3.2.2] non-3-yl) furo [2,3-c] pyridine-5-carboxamide fumarate Example 1 (vi) Was obtained as a white solid: ¹ H NMR (CD ₃ 0D) δ 8.9, 8.4, 8.1, 7.1, 6.7, 4.8-4.7, 3.8, 3.7-3.6, 3.5-3.3, 2.4, 2.2-2.0.

Example 2 (i): N-[(exo-1-azabicyclo [2.2.1] hept-3-yl] furo [3,2-c] pyridine-6-carboxamide:

3-bromofuran (8.99 mL, 100.0 mmol) was dissolved in DMF (8.5 mL), cooled to 0 ° C., treated dropwise with POCl ₃ (9.79 mL, 105.0 mmol) and stirred at room temperature for 1 hour. Then heated to 80 ° C. for 2 hours. The mixture was cooled to rt, poured into ice (1 kg) and neutralized to pH 9 by solid K ₂ CO ₃ . The mixture was stirred for 1 h, extracted with Et ₂ O (3 × 500 mL), dried over K ₂ CO ₃ and concentrated to give an earthy brown oil. The crude material was chromatographed with 600 g of slurry-packed silica gel eluted with 6% EtOAc / hexanes (4L), 8% EtOAc / hexanes (2L), 10% EtOAc / hexanes (1L) and finally 20% EtOAc / hexanes. . The appropriate fractions were combined and concentrated in vacuo to yield 14.22 g (81%) of 3-bromo-2-furaldehyde as a yellow oil. MS (EI) m / z: 174 (M &lt; + &gt;).

3-bromo-2-furaldehyde (14.22 g, 81.3 mmol) was combined with ethylene glycol (6.55 mL, 117.4 mmol) and para-toluene sulfonic acid monohydrate (772 mg, 4.06 mmol) in benzene (200 mL), and Heated at reflux for 5 hours with a Dean-Stark trap.

Further ethylene glycol (1.64 mL, 29.41 mmol) and benzene (150 mL) were added and the solution was heated for a further 2 hours. The mixture was cooled to rt, treated with saturated NaHCO ₃ and stirred for 0.5 h. The phases were separated and the organic phase was dried over Na ₂ SO ₄ and concentrated to give a brown oil (18.8 g). The crude material was chromatographed with 700 g of slurry-pack silica gel eluting with 15% EtOAc / hexanes. Appropriate fractions were combined and concentrated in vacuo to yield 16.45 g (92%) of 2- (3-bromo-2-furyl) -1,3-dioxolane as a sulfur-orange oil. MS (EI) m / z: 218 (M ⁺ ).

2- (3-bromo-2-furyl) -1,3-dioxolane (438 mg, 2.0 mmol) was dissolved in Et ₂ O (5 mL) in a flask dried under nitrogen, cooled to -78 ° C, The solution was added dropwise with tert-butyllithium (2.59 mL, 4.4 mmol) and stirred for 1 hour. DMF (178 μl, 2.3 mmol) in Et ₂ 0 (2 mL) was added dropwise and the mixture was stirred at −78 ° C. for 4 hours, then treated with oxalic acid dihydrate (504 mg, 4.0 mmol), followed by water ( 2 mL). The cold bath was removed and the mixture was allowed to warm to room temperature over 1 hour. The mixture was diluted with water (20 mL) and EtOAc (20 mL), the layers separated and the aqueous layer extracted with EtOAc (1 × 20 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated to give a yellow oil. The crude material was chromatographed with 12 g of slurry-pack silica gel eluting with 15% EtOAc / hexanes. Appropriate fractions were combined and concentrated in vacuo to give 228 mg (68%) of 2- (1,3-dioxolan-2-yl) -3-furaldehyde as light yellow oil. MS (EI) m / z: 168 (M ⁺ ).

Combine 2- (1,3-dioxolan-2-yl) -3-furaldehyde (2.91 g, 17.31 mmol) with formic acid (17 mL, 451 mmol) and water (4.25 mL) and stir at room temperature for 18 hours It was. The mixture was slowly transferred to a solution of NaHCO ₃ (45 g, 541 mmol) in water (600 mL) and then stirred for 0.5 h. EtOAc (200 mL) was added, the layers were separated and the aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give a yellow oil (3.28 g). The crude material was chromatographed with 90 g of slurry-pack silica gel eluting with 20% EtOAc / hexanes, the appropriate fractions were combined and concentrated to 2.45 g of furan-2,3-dicarbaldehyde slightly contaminated with ethylene glycol diformate. Was obtained as a yellow oil. ¹ H NMR (CDCl ₃ ): δ 7.00 (d, J = 2 Hz, 1 H), 7.67 (d, J = 2 Hz, 1 H), 10.07 (s, 1 H), 10.49 (s, 1 H) ppm.

Methyl (acetylamino) (dimethoxyphosphoryl) acetate (2.34 g, 9.8 mmol) is dissolved in CHCl ₃ (40 mL), treated with DBU (1.46 mL, 9.8 mmol), stirred for 5 minutes, and then CHCl To a 0 ° C. solution of furan-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in ₃ (80 mL) was added dropwise. The mixture was stirred for 2.5 hours, the cooling bath was removed, then stirred at room temperature for 5.5 hours and finally at 50 ° C. for 24 hours. The mixture was concentrated in vacuo to give a yellow-oily solid (6.66 g). The crude material was chromatographed with 100 g of slurry-pack silica gel standard eluting with 65% EtOAc / hexanes. Appropriate fractions were combined and concentrated in vacuo to yield 1.30 g (82%) of methyl furo [3,2-c] pyridine-6-carboxylate as a yellow solid. MS (EI) m / z: 177 (M ⁺ ).

Methyl furo [3,2-c] pyridine-6-carboxylate (1.55 g, 8.74 mmol) is dissolved in MeOH (30 mL) and H ₂ 0 (15 mL) and treated with 3N NaOH (6.4 mL). And stirred at room temperature for 7 hours. The mixture was concentrated to dryness, dissolved in H ₂ O (10 mL) and acidified to pH 2 with concentrated HCl. The solution was concentrated to dryness, suspended in a small amount of water (7 mL) and the resulting solid collected through filtration (lot A). The filtrate was concentrated, triturated with water (3 mL) and the resulting solid collected through filtration (lot B). The filtrate from lot B was concentrated and performed without further purification as an acid / salt mixture (lot C). Both Lot A and Lot B were dried in a vacuum oven at 50 ° C. for 18 hours to puro [3,2-c] pyridine-6-carboxylic acid for 690 mg (48%) for Lot A and 591 for Lot B. mg (42%) was obtained as a yellow solid. MS (CI) m / z: 164 (M + H ⁺ ).

Examples 2 (i), 2 (ia), 2 (ii), 2 (iii), 2 (iv) and 2 (vi) can be prepared without causing significant changes following the coupling procedure discussed herein. .

Example 2 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [3,2-c] pyridine-6-carboxamide.

Example 2 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide.

Example 2 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide.

Example 2 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide.

Example 2 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide: in coupling The yield was 94%. ¹ H NMR (400 MHz, CD ₃ 0D) δ 9.30, 8.75-8.80, 8.35-8.45, 7.35-7.45, 4.65-4.80, 3.25-3.80, 2.85-2.95, 2.30-2.45, 2.10-2.25, 1.95-2.10.

Example 2 (vi): N- (1-azabicyclo [3.2.2] non-3-yl) furo [3,2-c] pyridine-6-carboxamide.

Example 3 (i): N- (1-azabicyclo [2.2.1] -hept-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide:

Oxalyl chloride (3.1 mL, 35 mmol) was dissolved in 200 mL of CH ₂ Cl ₂ in a flask dried under N ₂ . The flask was placed in a dry ice / acetone bath at −78 ° C., DMSO (4.95 mL, 70 mmol) in 10 mL of CH ₂ Cl ₂ was added dropwise and the mixture stirred for 20 minutes. (7-chlorofuro [2,3-c] pyridin-5-yl) methanol ( C4 ) (5.5 g, 30 mmol) in 10 mL of CH ₂ Cl ₂ is added and the reaction is stirred at -78 ° C for 30 min It was. Then TEA (21.3 mL, 153 mmol) was added. The reaction was stirred for 30 min in a dry ice / acetone bath, the ice bath was replaced with a dry ice / acetone bath, the reaction was stirred for 1 h and washed with 100 mL of 1: 1 saturated NaCl / NaHCO ₃ . The organic layer was dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo to afford 7-chlorofuro [2,3-c] pyridine-5-carbaldehyde ( C6 ) as a pale yellow solid (yield 97%). It was. MS (EI) for C ₈ H ₄ ClN0 ₂ m / z: 181 (M) ⁺ .

C6 (3.0 g, 16.5 mmol) was dissolved in 40 mL of DMSO. KH ₂ PO ₄ (561 mg, 4.1 mmol) in 6.5 mL of H ₂ O was added, followed by NaClO ₂ (2.6 g, 23.1 mmol) in 24 mL of H ₂ O and the reaction was stirred at rt overnight. The reaction was diluted with 200 mL of H ₂ O, pH was adjusted to 9 with 2N NaOH, and any residual aldehyde was extracted with 3 × 50 mL of ether. The pH of the aqueous layer was adjusted to 3 with 10% aqueous HCl and extracted with 4 x 50 mL of EtOAc. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to give a white solid. The solid was washed with ether and dried to give 7-chlorofuro [2,3-c] pyridine-5-carboxylic acid ( C7 ) (yield 55%). MS (CI) for C ₈ H ₄ ClN0 ₃ , m / z: 198 (M + H).

C7 (980 mg, 4.98 mmol) was dissolved in 75 mL of MeOH containing 500 mg of 20% palladium hydroxide on carbon in a 250 mL Parr shake bottle. The reaction mixture was hydrogenated at 20 PSI for 24 hours. The catalyst was removed by filtration and the filtrate was laid out in vacuo to yield a white solid. The solid was dissolved in MeOH and loaded into 20 mL of Dowex 50W-X2 ion exchange resin (hydrogen), which had been previously washed with MeOH. The column was eluted with 50 mL of MeOH followed by 150 mL of 5% TEA in MeOH to give 2,3-dihydrofuro [2,3-c] pyridine-5-carboxylic acid ( C8 ) (yield 74%). HRMS (FAB) theory for C ₈ H ₇ NO ₃ + H: 166.0504, found 166.0498 (M + H).

Example 3 (ia) can be prepared according to the coupling procedure discussed herein using C8 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 3 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5- Carboxamide.

Example 3 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5- Carboxamide.

Example 3 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide.

Example 3 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide.

Example 3 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5- Carboxamide.

Example 3 (vi): N- (1-azabicyclo [3.2.2] non-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide.

Example 4 (i): N- (1-azabicyclo [2.2.1] hept-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide:

Example 4 (i) converts exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine to 7-chlorofuro [2,3-c] pyridine-5-carboxylic acid ( Obtained by coupling with C7 ).

The following examples can be prepared according to the coupling procedure discussed herein.

Example 4 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide .

Example 4 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide .

Example 4 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide.

Example 4 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide.

Example 4 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-chlorofuro [2, 3-c] pyridine-5-carboxamide .

Example 5 (i): N- (1-azabicyclo [2.2.1] hept-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5- Carboxamides:

2-Chloro-6- (hydroxymethyl) -4-iodo-3-pyridinol ( C2 ) (6.3 g, 22 mmol) was dissolved in 30 mL of DMF in a dried flask under N ₂ . The flask was placed in an ice bath and 60% sodium hydride in inorganic oil (880 mg, 22 mmol) was added. The reaction was stirred for 30 minutes while maintaining the flask in an ice bath. After the ice bath was removed for 30 minutes, the flask was placed back in the ice bath to cool the reaction. 3-bromo-2-methylpropene (23.1 mmol) was added and the reaction was stirred at rt overnight. The reaction was diluted with 150 mL of EtOAc and washed with 4 x 50 mL of 50% saturated 1: 1 NaCl / NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to give a pale oil which was crystallized from hexane to give (6-chloro-4-iodo-5-[(2-methyl-2- Propenyl) oxy] -2-pyridinyl) methanol ( C19 ) (yield 86%) was obtained. HRMS (FAB) theory for C ₁₀ H ₁₁ ClINO ₂ + H: 339.9603, found 339.9604 (M + H).

C19 (6.3 g, 18.9 mmol), sodium formate (1.49 g, 21.8 mmol), TEA (8 mL, 57.2 mmol), palladium acetate (202 mg, 0.9 mmol) and tetra (n-butyl) ammonium chloride (5.25 g , 18.9 mmol) was added to 30 mL of DMF in a flask dried under N ₂ . The reaction was warmed to 60 ° C. for 5 hours, poured into 150 mL of EtOAc and washed with 4 × 50 mL of 50% saturated 1: 1 NaCl / NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to give a pale oil. Crude was chromatographed with 40 g of silica gel (Biotage) eluting with 30% EtOAc / hexanes (7-chloro-3,3-dimethyl-2,3-dihydrofuro [2,3-c] Pyridin-5-yl) methanol ( C20 ) (yield 54%) was obtained. MS (EI) for C ₁₀ H ₁₂ ClN0 ₂ , m / z: 213 (M) ⁺ .

In a 250 mL Parr shake bottle, C20 (2.11 g, 9.9 mmol) and 600 mg of 10% Pd / C catalyst were placed in 30 mL EtOH. 2N NaOH (5 mL, 10 mmol) was then added and the mixture was hydrogenated at 20 PSI for 2.5 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to give an aqueous residue. Saturated NaHCO ₃ (20 mL) was added to the residue and extracted with 4 × 20 mL of CH ₂ Cl ₂ . The combined organic layers were dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo (3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridin-5-yl) methanol ( C21 ) (Yield 92%) was obtained. MS (EI) for C ₁₀ H ₁₃ N0 ₂ , m / z: 179 (M) ⁺ .

Oxalyl chloride (869 μl, 9.9 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ in a flask dried under N ₂ . The flask was placed in a dry ice / acetone bath at −78 ° C., then DMSO (1.41 mL, 19.8 mmol) in 5 mL of CH ₂ Cl ₂ was added dropwise and the mixture was stirred for 20 minutes. C21 (1.53 g, 8.5 mmol) in 5 mL of CH ₂ Cl ₂ was added and the reaction was stirred at −78 ° C. for 30 minutes. TEA (5.9 mL, 42.5 mmol) was added and the reaction stirred at -78 ° C for 20 min. The dry ice / acetone bath was removed and the reaction stirred for 1 hour and the reaction washed with 25 mL saturated NaHCO ₃ . The organic layer was dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo to give an orange solid. The crude material was chromatographed with 40 g of silica gel (Biotage) eluting with 25% EtOAc / hexanes to give 3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carbaldehyde ( C22) (yield 92%) was obtained. MS (EI) for C ₁₀ H ₁₁ N0 ₂ , m / z: 177 (M) ⁺ .

C22 (1.35 g, 7.62 mmol) was dissolved in 40 mL of THF, 20 mL of t-butanol and 20 mL of H ₂ O. KH ₂ PO ₄ (3.11 g, 22.9 mmol) and NaClO ₂ (2.58 g, 22.9 mmol) were added and the reaction was stirred at rt over the weekend. The reaction was concentrated in vacuo to give a residue. The residue was partitioned between 20 mL of water and CH ₂ Cl ₂ (2 × 50 mL). The combined organic layers were dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford crude 3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carboxylic acid ( C23 ) (yield 99%). HRMS (FAB) theory for C ₁₀ H ₁₁ NO ₃ + H: 194.0817, found 194.0808 (M + H).

Example 5 (i) can be obtained by coupling C23 with exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine using the coupling procedure discussed herein. .

The following examples can be prepared according to the coupling procedure discussed herein.

Example 5 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3- c] pyridine-5-carboxamide.

Example 5 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3- c] pyridine-5-carboxamide.

Example 5 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5- Carboxamide.

Example 5 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5- Carboxamide.

Example 5 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3- c] pyridine-5-carboxamide.

Example 6 (i): N- (1-azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide:

2-chloro-6- (hydroxymethyl) -4-iodo-3-pyridinol ( C2 ) (4.6 g, 16 mmol), propargyl trimethylsilane (2 g, 17.8 mmol), bis (triphenylforce) Pin) palladium dichloride (156 mg, 0.21 mmol), copper iodide (122 mg, 0.64 mmol) and piperidine (3.52 mL, 26.6 mmol) were added to 25 mL of DMF in a flask dried under N ₂ . The mixture was warmed to 45 ° C for 7 h, stirred at rt overnight, and diluted with 150 mL of EtOAc. The mixture was washed with 50% saturated 1: 1 NaCl / NaHC0 ₃ 4 x 50 mL. The organic layer was dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give an amber oil. The crude was eluted with 35% EtOAc / hexanes and chromatographed with 40 g of silica gel (7-chloro-2-methylfuro [2,3-c] pyridin-5-yl) methanol ( C24 ) (yield 24%) Obtained. MS (CI) for C ₉ H ₈ ClNO ₂ , m / z: 198 (M + H).

In a 250 mL Parr shake bottle, C24 (2.0 g, 10.8 mmol) was added to 500 mg of 10% Pd / C catalyst in 25 mL EtOH. 2N NaOH (6 mL, 12 mmol) was added and the reaction was hydrogenated at 20 PSI for 6 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give an aqueous residue. The residue was partitioned between 50 mL of 50% saturated NaCl and 30 mL of CH ₂ Cl ₂ . The organic layer was dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo to afford (2-methylfuro [2,3-c] pyridin-5-yl) methanol ( C25 ) (yield 77%). MS (CI) for C ₉ H ₉ NO ₂ , m / z: 164 (M + H).

Oxalyl chloride (784 μl, 8.9 mmol) was dissolved in 25 mL of CH ₂ Cl ₂ in a flask dried under N ₂ . The flask was placed in a dry ice / acetone bath at −78 ° C. and DMSO (1.26 mL, 17.8 mmol) in 5 mL of CH ₂ Cl ₂ was added. The mixture was stirred for 20 minutes and C25 (1.53 g, 8.5 mmol) in 5 mL of CH ₂ Cl ₂ was added. The reaction was stirred for 1 hour, TEA (5.9 mL, 42.5 mmol) was added and the reaction stirred at -78 ° C for 30 minutes. The flask was placed in an ice bath and the reaction stirred for 1 hour. The reaction was washed with 50 mL of saturated NaHCO ₃ . The organic layer was dried over anhydrous K ₂ CO ₃ , filtered and concentrated in vacuo to give a tan solid. The crude was chromatographed with 40 g of silica gel (Biotage) eluting with 25% EtOAc / hexanes to afford 2-methylfuro [2,3-c] pyridine-5-carbaldehyde ( C26 ) (yield 99%). Obtained. MS (EI) for C ₉ H ₇ NO ₂ , m / z: 161 (M) ⁺ .

C26 (1.15 g, 7.1 mmol) was dissolved in 40 mL of THF, 20 mL of t-butanol and 20 mL of H ₂ O. 2-methyl-2-butene (6.5 mL, 57.4 mmol) was added, followed by KH ₂ P0 ₄ (3.11 g, 22.9 mmol) and NaCl0 ₂ (2.58 g, 22.9 mmol). The reaction was stirred for 6 hours at room temperature. The reaction was concentrated in vacuo. Water (20 mL) was added to the residue to leave a white solid. The white solids were combined, washed with water then ether and dried to afford 2-methylfuro [2,3-c] pyridine-5-carboxylic acid ( C27 ) (yield 70%). MS (EI) for C ₉ H ₇ NO ₃ , m / z: 177 (M) ⁺ .

Example 6 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C27 .

The examples can be prepared according to the coupling procedure discussed herein.

Example 6 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide .

Example 6 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide .

Example 6 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide.

Example 6 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide.

Example 6 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide .

Example 7 (i): Exo-4- (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-car Voxamide / Fumarate:

2-chloro-6- (hydroxymethyl) -4-iodo-3-pyridinol ( C2 ) (7.14 g, 25.0 mmol) is dissolved in DMF (50 mL) in a flask dried under N ₂ and sodium hydride (60% dispersion in inorganic oil) (1.0 g, 25.0 mmol) was added and the reaction was stirred at rt for 1 h. Allyl bromide (2.38 mL, 27.5 mmol) is added and the reaction mixture is stirred at rt for 48 h. The mixture was diluted with EtOAc (50 mL) and washed with 4 x 25 mL of a 50% saturated solution of 1: 1 NaCI / NaHCO ₃ . The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give a white solid. The solid was washed with hexanes and dried to give 3- (allyloxy) -2-chloro-6- (hydroxymethyl) -4-iodopyridine ( C50 ) as a white solid (yield 68%). MS (EI) for C ₉ H ₉ ClIN0 ₂ m / z: 325 (M) ⁺ .

C50 (5.51 g, 16.9 mmol) was suspended in benzene (30 mL) in a dry flask under N ₂ . Azo (bis) isobutyryl nitrile (289 mg, 1.8 mmol) was added, the mixture was quickly heated to reflux and tributyltin hydride (4.91 mL, 18.2 mmol) in benzene (10 mL) was added. The solution was refluxed for 1.5 h, cooled to rt and concentrated in vacuo. The resulting residue was chromatographed with 125 g of slurry-pack silica gel eluting with EtOAc / hexane (20% -60%) concentration (7-chloro-3-methyl-2,3-dihydrofuro [2,3- c] pyridin-5-yl) methanol ( C51 ) was obtained as a white solid (89% yield). MS (ESI) for C ₉ H ₁₀ ClN0 ₂ + H, m / z: 200.1 (M + H).

C51 (3.00 g, 15.0 mmol) was added to 20% palladium hydroxide (800 mg) and 2N NaOH (9.2 mL, 18.2 mmol) on carbon in a Parr shake bottle. The mixture was hydrogenated at 20 PSI for 3 hours, filtered through celite and concentrated in vacuo to give a residue. The resulting residue was partitioned between H ₂ 0 (50 mL) and CH ₂ Cl ₂ (4 × 30 mL). The combined organic layers were dried over MgS0 ₄ , filtered and concentrated to give a colorless oil which was left to solidify (3-methyl-2,3-dihydrofuro [2,3-c] pyridin-5-yl) methanol 2.50 g (yield> 100%) of ( C52 ) were obtained as a white crystalline solid. MS (EI) for C ₉ H ₁₁ N0 ₂ m / z: 165 (M) ⁺ .

C52 (2.48 g, 15.03 mmol) was dissolved in pyridine (15 mL), acetic anhydride (4.18 mL, 45.09 mmol) was added and stirred at rt for 16 h under N ₂ . The reaction was concentrated in vacuo, the residue diluted with EtOAc (75 mL), washed with 50% saturated NaHCO ₃ (4 × 30 mL) and dried over MgSO ₄ . The organic layer was filtered and concentrated in vacuo to give (3-methyl-2,3-dihydrofuro [2,3-c] pyridin-5-yl) methyl acetate ( C53 ) as a colorless oil (yield 92%). . MS (EI) for C ₁₁ H ₁₃ NO ₃ , m / z: 207 (M) ⁺ .

C53 (2.85 g, 13.8 mmol) was dissolved in dioxane (100 mL), 2,3,5,6-tetrachlorobenzoquinone (3.72 g, 15.1 mmol) was added and the reaction heated to reflux for 17 h. . The reaction was concentrated in vacuo. The resulting brown solid was washed with 1: 1 EtOAc / ether (50 mL) and insoluble material was removed by filtration. The filtrate was concentrated to a brown solid, dissolved in MeOH (50 mL), treated with 2N NaOH (16 mL, 32 mmol) and stirred at rt for 1 h. The mixture was concentrated to dryness, dissolved in 1N NaOH (75 mL) and extracted with CH ₂ Cl ₂ (4 × 50 mL). The combined organic layers were dried over K ₂ CO ₃ , filtered and concentrated to give a white solid (2.0 g). The crude material was adsorbed onto silica gel (4 g) and chromatographed with 40 g of a standard biotage column eluting with 90% EtOAc / hexanes to (3-methylfuro [2,3-c] pyridin-5-yl) methanol ( C54 ) was obtained as a white solid (84% yield). MS (EI) for C ₉ H ₉ NO ₂ , m / z: 163 (M) ⁺ .

Oxalyl chloride (1.16 mL, 13.2 mmol) was added to CH ₂ Cl ₂ (30 mL) in a flask dried under N ₂ in a dry ice / acetone bath at −78 ° C. DMSO (18.80 mL, 26.5 mmol) was added slowly. The solution was stirred for 20 minutes and C54 (1.88 g, 11.5 mmol) was added. The mixture was stirred at -78 ° C for 1 hour and then at 0-5 ° C for 30 minutes. The material was washed with saturated NaHCO ₃ (75 mL), dried over K ₂ CO ₃ , filtered and concentrated in vacuo to give a yellow solid (3.23 g). The crude material was adsorbed onto silica gel (6 g) and chromatographed with 40 g of a standard biotage column eluting with 25% EtOAc / hexanes to 3-methylfuro [2,3-c] pyridine-5-carbaldehyde ( C55 ) was obtained as a white solid (72% yield). MS (EI) for C ₉ H ₇ NO ₂ , m / z: 161 (M) ⁺ .

C55 (1.33 g, 8.28 mmol) is dissolved in THF (50 mL), tert-butylalcohol (25 mL) and H ₂ 0 (25 mL) under N ₂ , NaCl0 ₂ (2.81 g, 24.84 mmol) and KH ₂ P0 ₄ (2.25 g, 16.56 mmol) was added. The reaction mixture was stirred overnight at room temperature, concentrated to dryness, dissolved in 50% saturated brine (60 mL) and extracted with ether (3 ×). TLC of the extract showed residual aldehyde as well as acid and the organic or aqueous layers were combined and basified to pH 10 with NH ₄ 0H. The layers were separated and the residual aldehyde was extracted with additional ether. The aqueous layer was acidified to pH 3 with concentrated HCl and then extracted with CH ₂ Cl ₂ (4 ×). A large amount of acid remained in the aqueous layer and the aqueous layer was concentrated to dryness. The solid was triturated with CHCl ₃ (4 ×) and then with 10% MeOH / CH ₂ Cl ₂ (4 ×) to extract much acid from the supernatant. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a tan solid (1.69 g, isolation yield> 100%). The solid was diluted with CHCl ₃ and heated to reflux for 3 hours. The flask was removed from the heat source, cooled slowly and filtered. The filtrate was concentrated to give a tan solid (1.02 g). The solid was triturated with ether, filtered and dried to give 3-methylfuro [2,3-c] pyridine-5-carboxylic acid ( C56 ) as a light tan solid (yield 51%). MS (CI) for C ₉ H ₇ NO ₃ , m / z: 178 (M + H).

Example 7 (i) comprises coupling the exo- (4S)-[2.2.1] -3-amine with C56 and then forming a fumarate salt as outlined in each of steps 1a and 1b to remove the compound of Example 7 ( i) was obtained in a yield of 77%. MS (ESI) m / e 272 (M + H) for C ₁₅ H ₁₈ N ₃ O ₂ .

Example 7 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide The above examples can be prepared according to the coupling procedure discussed herein.

Example 7 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-methylfuro [2, 3-c] pyridine-5-carboxamide The above examples can be prepared according to the coupling procedure discussed herein.

Example 7 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide: It can be prepared according to the coupling procedure discussed in.

Example 7 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide: It can be prepared according to the coupling procedure discussed in.

Example 7 (v): (exo) -N- [1-azabicyclo [3.2.1] oct-3-yl] -3-methylfuro [2,3-c] pyridine-5-carboxamide dihydro Chloride.

Mix a mixture of exo- [3.2.1] -amine (0.199 g, 1.00 mmol), C56 (0.177 g, 1.00 mmol), THF (15 mL), DIEA (0.53 mL, 3.02 mmol) and DMF (4 mL) Cooled in, and treated with HATU (0.380 g, 1.00 mmol). The mixture was warmed to ambient temperature and evaporated. The residue was diluted with CHCl ₃ and washed with aqueous NaOH (1N). The organic layer was dried (MgSO ₄ ), filtered, evaporated and the resulting oil was purified by flash column chromatography (1: 7: 90; concentrated NH ₄ 0H-MeOH-CHCl ₃ ). Bis-hydrochloride salt was formed and triturated with 2-propanol / acetone to give the desired product (0.110 g, 30%). MS (ESI) (M + H) ⁺ m / z = 286 for C ₁₆ H ₁₉ N ₃ 0 ₂ + H.

Example 8 (i): Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carbox Amide fumarate:

Starting with 1-chloro-2-butene and 2-chloro-6- (hydroxymethyl) -4-iodo-3-pyridinol ( C2 ), the corresponding 3-ethylfuro [2,3-c] Pyridine-5-carboxylic acid ( C60 ) was prepared. HRMS (FAB) theory for C ₁₀ H ₉ NO ₃ + H: 192.0661, found 192.0659 (M + H). Example 8 shows Example 8 (i) by coupling the exo-4 (S)-[2.2.1] -3-amine with C60 and then forming the fumarate salt described in each of steps 1a and 1b. Obtained in% yield. MS (ESI) m / e 286 (M + H) for C ₁₆ H ₂₀ N ₃ 0 ₂ .

The following examples can be prepared according to the coupling procedure discussed herein.

Example 8 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide .

Example 8 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide .

Example 8 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide.

Example 8 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide.

Example 8 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide .

Example 10 (i): N- (1-azabicyclo [2.2.1] hept-3-yl) -furo [2,3-b] pyridine-2-carboxamide:

Slowly (over 20 minutes) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) with ethyl glycolate (35.5 mL, 375 mmol) placing the flask in an ice bath under N ₂ Added. The mixture was allowed to warm to room temperature, stirred for 30 minutes and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) was added over 10 minutes. The reaction was warmed to 65 ° C. for 15 hours in an oil bath. The mixture is concentrated to dryness, the residue is dissolved in H ₂ 0 (500 mL), washed with hexane (500 mL), acidified to pH 3 with 5% HCl, and CHCl ₃ (4 × 400 mL). Extracted. The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a yellow solid. The solid was suspended in ether (200 mL) and heated on a steam bath until concentrated to 40 mL in volume. The material was crystallized overnight and filtered to give ethyl 3-hydroxyfuro [2,3-b] pyridine-2-carboxylate ( C40 ) as a pale orange solid (yield 41%). The filtrate was concentrated to give additional material. Recrystallization was performed twice in ether to give ( C40 ) as a light yellow solid (yield 7.3%). MS (EI) for C ₁₀ H ₉ NO ₄ , m / z: 207 (M) ⁺ .

C40 (207 mg, 1.0 mmol) was added to TEA (139 μl, 1.0 mmol) in CH ₂ Cl ₂ (5 mL) at room temperature, 2- [N, N-bis (trifluoromethylsulfonyl) amino] -5-chloropyridine (393 mg, 1.0 mmol) was added. The solution was stirred for 1 h at rt, diluted with EtOAc (25 mL) and washed with 50% saturated brine (2 × 15 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated to give a yellow oil which was left to solidify. The crude material was adsorbed onto silica gel (1.2 g) and chromatographed with 25 g of slurry-packed silica gel eluting with 20% EtOAc / hexanes to methyl 3-([(trifluoromethyl) sulfonyl] oxy) furo [2 , 3-b] pyridine-2-carboxylate ( C41 ) was obtained as a white crystalline solid (yield 98%). Analytical theory for C ₁₁ H ₈ F ₃ NO ₆ S: C, 38.94; H, 2. 38; N, 4.13. Found: C, 38.84; H, 2. 29; N, 4.11.

C41 (1.36 g, 4.0 mmol) was added to 10% Pd / C catalyst (68 mg) and NaHC0 ₃ (336 mg, 4.0 mmol) in EtOH (100 mL) / H ₂ 0 (5 mL) in a 250 mL Parr shake bottle. Added. The mixture was hydrogenated at 10 PSI for 5 hours, filtered and concentrated to give a residue. The residue was partitioned between 50% saturated NaHCO ₃ (80 mL) and EtOAc (80 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to give a colorless oil which was left to solidify (793 mg). The crude material was chromatographed with 40 g of slurry-pack silica gel eluting with 25% EtOAc / hexanes to give ethyl furo [2,3-b] pyridine-2-carboxylate ( C42 ) as a white solid (90% yield). It was. MS (EI) for C ₁₀ H ₉ NO ₃ , m / z: 191 (M) ⁺ .

C42 (758 mg, 3.96 mmol) was dissolved in MeOH (20 mL) and lithium hydroxide monohydrate (366 mg, 8.7 mmol) in H ₂ 0 6 mL was added under N ₂ . The reaction was stirred at rt for 2 h, concentrated to dryness, diluted with H ₂ 0 (5 mL) and acidified to pH 3 with 10% HCl. The resulting solids were combined by filtration, further washed with water and dried to give furo [2,3-b] pyridine-2-carboxylic acid ( C43 ) as a white solid (yield 97%). MS (EI) for C ₈ H ₅ NO ₃ , m / z: 163 (M) ⁺ .

Example 10 (i) can be obtained by coupling one of exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C43 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 10 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -furo [2,3-b] pyridine-2-carboxamide.

Example 10 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -furo [2,3-b] pyridine-2-carboxamide.

Example 10 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -furo [2,3-b] pyridine-2-carboxamide.

Example l0 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -furo [2,3-b] pyridine-2-carboxamide.

Example 10 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -furo [2,3-b] pyridine-2-carboxamide.

Example 10 (vi): N- (1-azabicyclo [3.2.2] non-3-yl) -furo [2,3-b] pyridine-2-carboxamide.

Example 11 (i): Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carr Voxamide / Fumarate:

3-isopropylfuro [2,3-c] pyridine-5-carboxylic acid using the method used in the preparation of the acid for Example 7 (i) without significant changeC70) 1-chloro-3-methyl-2-butene and 2-chloro-6- (hydroxymethyl) -4-iodo-3-pyridinol (C2To be prepared). C₁₁H₁₁O₃HRMS (FAB) theory for + H: 206.0817, found 206.0817 (M + H)⁺.

Example 11 (i) was coupled to exo- (4S)-[2.2.1] -3-amine with C70, followed by the formation of a fumarate salt as outlined in each of steps 1a and 1b. (i) was obtained in 89% yield. MS (ESI) for C ₁₇ H ₂₂ N ₃ 0 ₂ , m / z: 300 (M + H).

The following examples can be prepared according to the coupling procedure discussed herein:

Example 11 (ia): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carbox amides.

Example 11 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carbox amides.

Example 11 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide.

Example 11 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide.

Example 11 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carbox amides.

Example 12 (i): N- (1-azabicyclo [2.2.1] hept-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide:

Example 12 (i) added Example 4 (i) (0.72 mmol) and sodium thiomethoxide (0.79 mmol) to DMF (3 mL) and Example 4 (i) was not shown by TLC It can be obtained by stirring until. The reaction mixture is then diluted with MeOH, loaded into an AG 5OW-X2 resin (hydrogen) column, rinsed with MeOH, and the product eluted with about 5% TEA / MeOH solution on a column of AMBERJET 4400 OH resin. It was. The crude material can be further purified by chromatography on slurry-pack silica gel eluting with about 0.5% NH ₄ 0H / 8% MeOH / CH ₂ Cl ₂ .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 12 (-a): N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine- 5-carboxamide.

Example 12 (ii): N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5 Carboxamide.

Example 12 (iii): N- (2-azabicyclo [2.2.1] hept-5-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide.

Example 12 (iv): N- (2-azabicyclo [2.2.1] hept-6-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-7-carboxamide.

Example 12 (v): N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5 Carboxamide.

Example 13 (i): N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-2-carboxamide:

THF (200 mL) in the flask dried under N ₂ was cooled by placing in a dry ice / acetone bath at −78 ° C. Butyl lithium (125 mL, 200 mmol) was added dropwise, followed by dropwise addition of iodobenzene (11.19 mL, 100 mmol) in THF (10 mL). The solution was stirred at -78 ° C for 30 minutes. Idiisopropylamine (0.70 mL, 5 mmol) in THF (3 mL) and 2-chloropyridine (9.46 mL, 100 mmol) in THF (30 mL) were added dropwise successively, and the solution was added at -40 ° C for 1 hour. Stirred. Formyl piperidine (11.1 mL, 100 mmol) in THF (25 mL) was added dropwise and the solution was stirred at -40 ° C for 1 h. The reaction was quenched with 40 mL of 6N HCl, diluted with 250 mL of ether, and a small amount of sodium thiosulfate solution was added to remove iodine color. The solution was neutralized with saturated NaHCO ₃ , filtered and extracted with ether (3 × 150 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was chromatographed with 600 g of slurry-packed silica eluting with 20% EtOAc / hexanes to give 2-chloronicotinaldehyde ( C90 ) as a pale orange solid (yield 54%). MS (EI) for C ₆ H ₄ ClNO, m / z: 141 (M) ⁺ .

C90 (1.41 g, 10.01 mmol) was dissolved in DMF (10 mL) and H ₂ 0 (1 mL) under N ₂ . K ₂ CO ₃ (1.56 g, 11.27 mmol) and methyl thioglycolate (1.00 mL, 11.25 mmol) were added in portions. The reaction was stirred at 35 ° C. for 24 h, quenched with cold H ₂ O (75 mL) and placed in an ice bath to facilitate precipitation. The precipitate was isolated by filtration to give methyl-thieno [2,3-b] pyridine-2-carboxylate ( C101 ) as an orange powder (yield 40%). MS (EI) for C ₉ H ₇ NO ₂ S, m / z: 193 (M) ⁺ .

C101 (0.700 g, 3.63 mmol) was dissolved in MeOH (15 mL) and H ₂ O 3 mL. 2N NaOH (1.82 mL, 3.63 mmol) was added dropwise and the reaction was stirred at rt for 24 h. The reaction was concentrated in vacuo and H ₂ O (40 mL) was added to dissolve the residue. The resulting solution was acidified to pH 4 with concentrated HCl and the precipitate was isolated by filtration to give thieno [2,3-b] pyridine-2-carboxylic acid ( C102 ) as a white powder (yield 85%). . MS (EI) for C ₈ H ₅ NO ₂ S, m / z: 179 (M) ⁺ .

Example 13 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C102 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 13 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-2-carboxamide.

Example 13 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-2-carboxamide.

Example 13 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-2-carboxamide.

Example 13 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-2-carboxamide.

Example 13 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-b] pyridine-2-carboxamide.

Example 13 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-2-carboxamide.

Example 14 (i) : N- (l-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide:

2-nitrothiophene (33.76 g, 261.4 mmol) was suspended in concentrated HCl (175 mL) and heated to 50 ° C. Tin chloride (118.05 g, 523.2 mmol) was added in portions while the reaction temperature was maintained at 45-50 ° C. in an ice bath, and the ice bath was removed after the addition. The solution was cooled slowly to 30 ° C. over 1 hour. The solution was then cooled in an ice bath and filtered. The cake was washed with concentrated HCl (20 mL), dried in an air stream and washed with ether (50 mL) to give the hexachlorostannate salt of 2-aminothiophene as a brown solid (yield 26%).

3,3-dimethyl-2-formyl propionitrile sodium (3.33 g, 20.2 mmol) is described by Bertz, SH, et al., J. Org. Chem., 47, 2216-2217 (1982). Dissolve 3,3-dimethyl-2-formyl propionitrile sodium in MeOH (40 mL), hexachlorostanate salt of concentrated HCl (4 mL) and 2-aminothiophene (10.04) in MeOH (130 mL) g, 19.1 mmol) was slowly added dropwise to the mixture. After addition, the mixture was heated to reflux (80 ° C.) in an oil bath for 4 hours before MeOH (10 mL) and concentrated HCl (10 mL) were added. The reaction was refluxed for another 20 hours. The solution was cooled to rt and the reaction was concentrated in vacuo. The purple residue was dissolved in H ₂ 0 (60 mL) and the slurry was filtered. The cake was ground and stirred vigorously with 5% MeOH / CHCl ₃ (105 mL) while heating to 55 ° C. The mixture was cooled and filtered, and the organic layer was concentrated to give a green oil. The crude material was chromatographed through 130 g of slurry-packed silica eluting with 30% EtOAc / hexanes to convert thieno [2,3-b] pyridine-5-carbonitrile ( C105 ) to a light yellow solid (yield 24%). Got it. HRMS (FAB) calc'd for C ₈ H ₄ N ₂ S + H: 161.0173, found 161.0173 (M + H).

NaOH (0.138 g, 3.45 mmol) was added to a solution of C105 (0.503 g, 3.14 mmol) dissolved in 70% EtOH / H ₂ O (12 mL). The mixture was heated to reflux at 100 ° C. for 3 hours. The reaction was concentrated in vacuo and the residue was dissolved in H ₂ 0 (8 mL) and neutralized with concentrated HCl. The slurry was filtered and rinsed with ether. Initial NMR of the isolated material showed the presence of carboxamide intermediate, the material was suspended in 1M NaOH (6 mL) and stirred overnight. Water (10 mL) was added, the solution was extracted with ether (3 × 10 mL) and the mixture was neutralized with concentrated HCl. The slurry was filtered and rinsed with ether to give thieno [2,3-b] pyridine-5-carboxylic acid ( C106 ) as an off-white solid (yield 48%). MS (EI) for C ₈ H ₅ NO ₂ S, m / z: 179 (M) ⁺ .

Example 14 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C106 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 14 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide.

Example 14 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-5-carboxamide.

Example 14 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-5-carboxamide.

Example 14 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-5-carboxamide.

Example 14 (v) : N-((3R, SR) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-b] pyridine-5-carboxamide.

Example 14 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-5-carboxamide.

Example 15 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide:

2-nitrothiophene (12.9 g, 99.9 mmol) was dissolved in concentrated HCl (200 mL) and stirred vigorously at 30 ° C. Powder tin (25 g, 210 mmol) was added slowly in portions. Once the tin was completely dissolved, zinc chloride (6.1 g, 44.7 mmol) in EtOH (70 mL) was added in portions, the mixture was heated to 85 ° C. and malondialdehyde diethyl acetal (24 mL, in EtOH (30 mL) 100 mmol) was added. The solution was continued to stir at 85 ° C. for 1 hour and quenched by pouring ice (100 g). The pH of the mixture was adjusted to 10 with NH _{4 0} H and the resulting slurry was carefully filtered through celite overnight. The liquid was extracted with CHCl ₃ (3 × 300 mL) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a brown oil. The crude material was chromatographed with 250 g of slurry-packed silica eluting with 35% EtOAc / hexanes to give thieno [2,3-b] pyridine ( C110 ) as an orange oil (yield 26%). MS (EI) for C ₇ H ₅ NS, m / z: 135 (M) ⁺ .

C110 (3.47 g, 25.7 mmol) was dissolved in acetic acid (12 mL) and heated to 85 ° C. 30% hydrogen peroxide (9 mL) was added dropwise and the solution was stirred overnight. The reaction was cooled to room temperature and paraformaldehyde quenched using starch-iodine paper until the peroxide test appeared negative. The solution was diluted with H ₂ O (100 mL), neutralized with NaHCO ₃ and then extracted repeatedly with CHCl ₃ (12 × 80 mL, 6 × 50 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a brown solid. Crude was chromatographed through 70 g of slurry-packed silica eluting with 3.5% MeOH / CH ₂ Cl ₂ to give the thieno [2,3-b] pyridine-7-oxide ( C111 ) as a pale yellow solid (yield 22 %). MS (EI) for C ₇ H ₅ NOS m / z: 151 (M) ⁺ .

A 0.5 M solution of C111 (5 mL, 2.5 mmol) in CH ₂ Cl ₂ under N ₂ was diluted with CH ₂ Cl ₂ 8 mL. Dimethyl carbamyl chloride (0.27 mL, 2.9 mmol) was added dropwise and trimethylsilyl cyanide (0.388 mL, 2.9 mmol) was added via syringe. The reaction was stirred for 9 days and quenched with 10% K ₂ CO ₃ (10 mL). The layers were separated and the organic layer was isolated, dried over K ₂ CO ₃ , filtered and concentrated to give a brown solid. The crude material was chromatographed through 25 g slurry-pack silica eluting with 35% EtOAc / hexanes to convert thieno [2,3-b] pyridine-6-carbonitrile ( C112 ) to a light yellow solid (yield 100%). Got it. Calcd for C ₈ H ₄ N ₂ S: C, 59.98; H, 2.52; N, 17.49. Found: C, 59.91; H, 2.57; N, 17.43.

NaOH (398 mg, 9.95 mmol) was added in portions to a solution of C112 (674 mg, 4.2 mmol) in 70% EtOH / H ₂ 0 (20 mL). The solution was heated to reflux at 100 ° C. for 24 hours and the reaction concentrated in vacuo. The residue was dissolved in H ₂ 0 (15 mL) and washed with ether (3 × 10 mL). A precipitate was formed by adjusting the pH to 3.5 with concentrated HCl. The slurry was filtered to give thieno [2,3-b] pyridine-6-carboxylic acid ( C113 ) as a white solid (yield 45%). MS (EI) for C ₈ H ₅ NO ₂ S, m / z: 179 (M) ⁺ .

Example 15 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C113 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 15 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide.

Example 15 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide.

Example 15 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-6-carboxamide.

Example 15 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-6-carboxamide.

Example 15 (v) : N-((3R, SR) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide.

Example 15 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-6-carboxamide.

Example 16 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-2-carboxamide:

THF (200 mL) was cooled to −70 ° C. in a dry flask under N ₂ , and N-butyllithium (24.4 mL, 55.0 mmol) was added dropwise. The reaction was placed in an ice bath and DIA (7.71 mL, 55.0 mmol) in THF (20 mL) was added dropwise. The solution was again cooled to -70 ° C and 3-chloropyridine (4.75 mL, 50.0 mmol) in THF (20 mL) was added dropwise. The reaction was stirred at -70 ° C for 4 h and ethyl formate (4.44 mL, 55.0 mmol) in THF (20 mL) was added. The reaction was stirred for another 3 h at -70 ° C and quenched with H ₂ 0 (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a dark brown solid. The crude material was chromatographed through 250 g of slurry-packed silica eluting with 50% EtOAc / hexanes to give 3-chloroisonicotinaldehyde ( C120 ) as an off-white solid (yield 55%). MS (EI) for C ₆ H ₄ ClNO, m / z: 141 (M) ⁺ .

C120 (2.12 g, 14.9 mmol) was dissolved in DMF (75 mL) containing a small amount of H ₂ 0 (7.5 mL). Methyl thioglycolate (1.67 mL, 18.7 mmol) and K ₂ CO ₃ (2.59 g, 18.7 mmol) were added in portions and the mixture was stirred at 45 ° C. for 24 h. The reaction was quenched with cooled H ₂ 0 (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with 50% NaCl solution (3 × 150 mL), dried over MgSO ₄ , filtered and concentrated to give an orange solid. Crude was chromatographed through 40 g of slurry-packed silica eluting with 50% EtOAc / hexanes to afford ethyl thieno [2,3-c] pyridine-2-carboxylate ( C121 ) as a pale yellow solid (yield 22%). )

C121 (577 mg, 2.99 mmol) was combined with 2M NaOH (1.5 mL, 3.0 mmol) in MeOH (15 mL) and H ₂ O (1.5 mL). The reaction was stirred at rt for 24 h. The reaction was concentrated in vacuo and the residue dissolved in H ₂ O (75 mL). The solution was acidified to pH 3 with concentrated HCl. The slurry was filtered, washed with H ₂ O and ether and dried to give thieno [2,3-c] pyridine-2-carboxylic acid ( C122 ) as an off-white solid (yield 38%). HRMS (FAB) calc'd for C ₈ H ₅ NO ₂ S + H: 180.0119, found 180.0119 (M + H).

Example 16 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C122 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 16 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-2-carboxamide.

Example 16 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-c] pyridine-2-carboxamide.

Example 16 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-c] pyridine-2-carboxamide.

Example 16 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-c] pyridine-2-carboxamide.

Example 16 (v) : N-((3R, SR) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-c] pyridine-2-carboxamide.

Example 16 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-c] pyridine-2-carboxamide.

Example 17 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-2-carboxamide:

3-chloropyridine (9.5 mL. 99.9 mmol) was dissolved in acetic acid (35 mL) and heated to 98 ° C. 30% hydrogen peroxide (28 mL) was added dropwise and the reaction stirred at 98 ° C. for 5 hours. The reaction was cooled and paraformaldehyde was added so that a negative peroxide test was achieved using starch-iodine paper. The solution is concentrated in vacuo and the crude paste is slurry-pack eluted with 2% MeOH / CH ₂ Cl ₂ 4 L, 4% MeOH / CH ₂ Cl ₂ 2 L and finally 10% MeOH / CH ₂ Cl ₂ 1 L. Chromatography through 600 g of silica gave 3-chloropyridine 1-oxide ( C125 ) as a pale oil (yield 100%).

A 2 M solution of C125 (10 mL, 20 mmol) was further combined with 90 mL of CH ₂ Cl ₂ . Dimethylcarbamoyl chloride (2.03 mL, 22.0 mmol) was added dropwise, then trimethyl silylcyanide (2.93 mL, 22.0 mmol) was added via syringe. The reaction was stirred at rt for 10 days and quenched with 10% K ₂ CO ₃ (100 mL). The layers were separated and the organic layer was dried over K ₂ CO ₃ , filtered and concentrated to give an orange solid. The crude material was chromatographed through 160 g of slurry-packed silica eluting with 40% EtOAc / hexanes to give 3-chloropyridine-2-carbonitrile ( C126 ) as a white solid (59% yield). MS (EI) for C ₆ H ₃ ClN ₂ , m / z: 138 (M) ⁺ .

C126 (1.01 g, 7.29 mmol) and K ₂ CO ₃ (1.10 g, 7.96 mmol) were added to DMF (10 mL) and H ₂ 0 (1 mL). Methyl thioglycolate (0.709 mL, 7.93 mmol) was added dropwise and the solution was heated to 40 ° C and stirred for 3 h. The reaction was quenched with cooled H ₂ 0 (70 mL) and placed on ice to facilitate precipitation. The slurry was filtered and the cake dissolved in CHCl ₃ . The organic solution was dried over MgSO ₄ , filtered and concentrated to give methyl 3-aminothieno [3,2-b] pyridine-2-carboxylate ( C127 ) as a yellow solid (yield 84%). HRMS (FAB) calc'd for C ₉ H ₅ N ₂ 0 ₂ S + H: 209.0385, found 209.0383 (M + H).

C127 (0.919 g, 4.42 mmol) was dissolved in 50% hypophosphoric acid (35 mL) and cooled in an ice bath. Sodium nitrite (0.61 g, 8.84 mmol) was dissolved in a minimum amount of H ₂ 0, added dropwise to the previous solution, and the reaction stirred in an ice bath for 3 hours. The pH was adjusted to 7.9 with 3M NaOH and the solution extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give methyl thieno [3,2-b] pyridine-2-carboxylate ( C128 ) as a yellow solid (yield 44%). MS (EI) for C ₉ H ₇ NO ₂ S, m / z: 193 (M) ⁺ .

2M NaOH (0.8 mL, 1.6 mmol) and C128 (300 mg, 1.55 mmol) were added to MeOH (8 mL) and H ₂ 0 (1 mL) and stirred for 24 h. The reaction was concentrated in vacuo and the residue dissolved in H ₂ 0 (5 mL). The pH was adjusted to 3.5 with 5% HCl to produce a precipitate. The slurry was filtered and washed with ether to give thieno [3,2-b] pyridine-2-carboxylic acid ( C129 ) as a brown solid (yield 67%). HRMS (FAB) calc'd for C ₈ H ₅ NO ₂ S + H: 180.0119, found 180.0121 (M + H).

Example 17 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C129 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 17 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-2-carboxamide.

Example 17 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-2-carboxamide.

Example 17 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-2-carboxamide.

Example 17 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-2-carboxamide.

Example 17 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-2-carboxamide.

Example 17 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-2-carboxamide.

Example 18 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide:

Example 18 (i) couples exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with commercially available thieno [3,2-b] pyridine-5-carboxylic acids It can be obtained by ringing.

The following examples can be prepared according to the coupling procedure discussed herein:

Example 18 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide.

Example 18 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide.

Example 18 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-5-carboxamide.

Example 18 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-5-carboxamide.

Example 18 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide.

Example 18 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-5-carboxamide.

Example 19 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide:

Methyl 3-aminothiophene-2-carboxylate (1.52 g, 9.68 mmol) was dissolved in 2M NaOH (10 mL, 20 mmol) and heated to reflux in a 115 ° C. oil bath for 30 minutes. The mixture was cooled to rt, placed in an ice bath and carefully acidified with concentrated HCl. The slurry was filtered and rinsed with H ₂ 0 (25 mL). The cake was then dissolved in acetone (50 mL), dried over MgSO ₄ , filtered and concentrated to give a thick paste. The crude material was dissolved in 1-propanol (25 mL) and oxalic acid (0.90 g, 10.0 mmol) was added in portions. The mixture was heated at 38 ° C. for 45 min, cooled to rt and diluted with ether. The precipitate was isolated via filtration and washed with ether to give 3-amino-thiophene oxalate ( C135 ) as a downy white solid (yield 70%). HRMS (FAB) calc'd for C ₄ H ₅ NS + H: 100.0221, found 100.0229 (M + H).

3,3-dimethyl-2-formyl propionitrile sodium (5.38 g, 32.6 mmol) was dissolved in MeOH (60 mL) containing concentrated HCl (6 mL). C135 (6.16 g, 32.6 mmol) was suspended in MeOH (200 mL) and added dropwise to the acidic solution. The mixture was heated to reflux at 80 ° C. for 5 hours when further 20 mL of concentrated HCl and 20 mL of H ₂ O were added; The mixture was refluxed for another 12 hours. The mixture was concentrated in vacuo and the residue was dissolved in cold H ₂ O (100 mL). The resulting precipitate was filtered and dried to give thieno [3,2-b] pyridine-6-carbonitrile (C136) as a brown solid (yield 44%). HRMS (FAB) calc'd for C ₈ H ₄ N ₂ S + H: 161.0173, found 161.0170 (M + H).

C136 (1.99 g, 12.5 mmol) was dissolved in 70% EtOH / H ₂ O (20 mL) and NaOH (0.52 g, 13.0 mmol) was added in portions. The mixture was heated at 100 ° C. for 15 h and then cooled to rt. The mixture was concentrated in vacuo. The residue was dissolved in cooled H ₂ 0 (30 mL) and the solution was rinsed with ether (3 × 10 mL). The pH was adjusted to 3.5 with concentrated HCl to precipitate the desired product which was filtered off to give thieno [3,2-b] pyridine-6-carboxylic acid ( C137 ) as a tan solid (yield 77%). HRMS (FAB) calc'd for C ₈ H ₅ NO ₂ S + H: 180.0119, found 180.0118 (M + H).

Example 19 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C137 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 19 (i) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide.

Example 19 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide.

Example 19 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-6-carboxamide.

Example 19 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-6-carboxamide.

Example 19 (v) : N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide.

Example 19 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-6-carboxamide.

Example 20 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-2-carboxamide:

4-chloropyridine hydrochloride (15 g, 99.9 mmol) was stirred in 1: 1 saturated NaHC0 ₃ / ether 100 mL for 1 hour to remove the base. The layers were separated, the aqueous layer was extracted with ether (2 x 175 mL) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated to give an oil. THF (300 mL) was cooled to -70 ° C in a dry flask. N-butyllithium (105.1 mL, 168.2 mmol) was added dropwise and the mixture was placed in an ice bath. Diisopropylamine (23.6 mL, 168.4 mmol) in THF (50 mL) was added dropwise, the yellow solution was stirred for 30 minutes, and the reaction was cooled to -70 ° C. Base removed 4-chloropyridine oil (9.55 g, 84.1 mmol) was dissolved in THF (50 mL) and added dropwise to the cooled yellow solution and turned black after addition. The reaction was stirred at -70 ° C for 2 hours. Ethyl formate (13.6 mL, 168.3 mmol) in THF (25 mL) was then added dropwise to the black solution at -70 ° C. After 2 hours, the reaction was warmed to -10 ° C and quenched with water (450 mL). The layers were separated and the aqueous layer was extracted with ether (3 x 200 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo to afford an oil. The crude material was chromatographed through 320 g of slurry-packed silica eluting with 30% EtOAc / hexanes to give 4-chloropyridine-3-carboxaldehyde ( C140 ) as an orange oil, which was solidified under vacuum to give an orange solid (yield) 21%) was obtained.

C140 (2.53 g, 17.9 mmol) was dissolved in DMF (20 mL) and H ₂ 0 (2 mL). K ₂ CO ₃ (2.97 g, 21.5 mmol) and methyl thioglycolate (1.92 mL, 21.5 mmol) were added in portions. The reaction was stirred at 45 ° C. for 24 hours and then quenched with cooled H ₂ O (100 mL) and the flask placed on ice to facilitate precipitation. The precipitate was isolated by filtration and dried to give methyl thieno [3,2-c] pyridine-2-carboxylate ( C141 ) as a white solid (yield 92%). MS (EI) for C ₉ H ₇ NO ₂ S, m / z: 193 (M) ⁺ .

C141 (2.65 g, 13.7 mmol) was dissolved in MeOH (70 mL) and H ₂ 0 (5 mL). 2N NaOH (6.86 mL, 13.7 mmol) was added dropwise and the reaction was stirred at rt for 24 h. The reaction was concentrated in vacuo and H ₂ 0 (150 mL) was added to dissolve the residue. The resulting salt solution was concentrated to pH 3.5 using concentrated HCl, and the precipitate was isolated by filtration and dried to give thieno [3,2-c] pyridine-2-carboxylic acid ( C142 ) as a white powder (yield 57 %). HRMS (FAB) calc'd for C ₈ H ₅ NO ₂ S + H: 180.0119, found 180.0124 (M + H).

Example 20 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C142 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 20 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-2-carboxamide.

Example 20 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-c] pyridine-2-carboxamide.

Example 20 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-c] pyridine-2-carboxamide.

Example 20 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide.

Example 20 (v) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide.

Example 20 (vi) N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide.

Example 21 (i) : Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide Fumarate:

Glyoxylic acid monohydrate (20.3 g, 221 mmol) and benzyl carbamate (30.6 g, 202 mmol) were added to ether (200 mL). The solution was stirred for 24 hours at room temperature. The resulting thick precipitate was filtered and the residue was washed with ether to give ([(benzyloxy) carbonyl] amino) (hydroxy) acetic acid ( C150 ) as a white solid (yield 47%). MS (CI) for C ₁₀ H ₁₁ N0 ₅ + H, m / z: 226 (M + H).

C150 (11.6 g, 51.5 mmol) was dissolved in anhydrous MeOH (120 mL) and cooled in an ice bath. Concentrated sulfuric acid (2.0 mL) was added dropwise carefully. The ice bath was removed and the solution stirred for 2 days. The reaction was quenched by pouring saturated NaHCO ₃ solution (400 mL) into a mixture of 500 g of ice. The solution was extracted with EtOAc (3 x 300 mL) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a pale oil which was left to crystallize to methyl ([(benzyloxy) carbonyl] amino). (Methoxy) acetate ( C151 ) was obtained as a white solid (yield 94%). Analysis calculated for _{C l2 H 15 NO 5: C} , 56.91; H, 5.97; N, 5.53. Found: C, 56.99; H, 6.02; N, 5.60.

C151 (11.76 g, 46.4 mmol) was dissolved in toluene (50 mL) under N ₂ and heated to 70 ° C. Phosphorus trichloride (23.2 mL, 46.4 mmol) was added dropwise by syringe, and the solution was stirred at 70 ° C for 18 h. Trimethyl phosphite (5.47 mL, 46.4 mmol) was then added dropwise and stirred at 70 ° C. for 2 more hours. The mixture was concentrated in vacuo to give an oil, the crude was dissolved in EtOAc (100 mL) and washed with saturated NaHCO ₃ (3 × 50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 30 mL volume. The remaining solution was vigorously stirred with the addition of hexanes until a precipitate formed. The precipitated solid was filtered off to obtain methyl ([(benzyloxy) carbonyl] amino) (dimethoxyphosphoryl) acetate ( C152 ) as a white solid (yield 84%). MS (EI) for C ₁₃ H ₁₈ NO ₇ P, m / z: 331 (M) ⁺ .

C152 (12.65 g, 38.2 mmol) and acetic anhydride (9.02 mL, 95.5 mmol) in MeOH (100 mL) were added to the Parr flask. The solution was hydrogenated at 45 PSI for 3 hours with 10% Pd / C catalyst (0.640 g). The catalyst was filtered off and the filtrate was concentrated in vacuo to give an oil. The oil was placed under reduced pressure and solidified under reduced pressure. The white residue was dissolved in a small amount of EtOAc and stirred vigorously with addition of pentane until a precipitate began to form. The precipitate was filtered off to obtain methyl (acetylamino) (dimethoxyphosphoryl) acetate (C153) as a white powder (yield 87%). MS (CI) for C ₇ H ₁₄ NO ₆ P, m / z: 240 (M + H).

2,3-thiophene dicarboxaldehyde (1.40 g, 9.99 mmol) was dissolved in CH ₂ Cl ₂ (100 mL) and the flask placed in an ice bath. C152 (2.63 g, 11.0 mmol) is dissolved in CH ₂ Cl ₂ (50 mL), 1,8-diazabicyclo [5.4.0] un-7-7-ene (1.65 mL, 11.0 mmol) is added, and this solution Was added dropwise to the cooled thiophene solution. The flask was placed in an ice bath and the reaction mixture was stirred for 1 hour and then at room temperature overnight. The reaction was concentrated in vacuo and the crude material was chromatographed through 300 g of slurry-pack silica eluting with 50% EtOAc / hexanes. Fractions were collected in two different groups to obtain the desired compound. Each group of fractions was combined separately and concentrated. Methyl thieno [2,3-c] pyridine-5-carboxylate ( C154 ) is obtained as a white solid (41% yield) in the first group of fractions, and methyl thieno [3,2 in the second group of fractions. -c] pyridine-6-carboxylate ( C155 ) was obtained as a yellow solid (yield 38%). MS (EI) for C 154 for C ₉ H ₇ NO ₂ S, m / z: 193 (M) ⁺ . MS (EI) for C 155 for C ₉ H ₇ NO ₂ S, m / z: 193 (M) ⁺ .

C154 (736 mg, 3.8 mmol) was dissolved in MeOH (16 mL) containing water (2 mL). 2M NaOH (2.0 mL, 4.0 mmol) was added dropwise and the solution was stirred at room temperature. After 2 days (the ester completely disappeared by TLC), the reaction was concentrated in vacuo. The residue was dissolved in H ₂ 0 (12 mL) and the pH was adjusted to 3.5 using 10% HCl. The precipitated solid was filtered off and the solid was rinsed with ether to give thieno [2,3-c] pyridine-5-carboxylic acid ( C156 ) as a white solid (yield 58%). HRMS (FAB) calc'd for C ₈ H ₅ NO ₂ S + H: 180.0119, found 180.0123 (M + H).

After coupling the exo- (4S)-[2.2.1] -3-amine with C156 , the fumarate salt was formed as described in steps 1a and 1b, respectively, to give Example 21 (i) in 84% yield. Got it. MS m / e for C ₄ H ₁₆ N ₃ OS (ESI): 274 (M + H).

Example 21 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide: present The examples can be prepared according to the coupling procedure discussed herein.

Example 21 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide: present The examples can be prepared according to the coupling procedure discussed herein.

Example 21 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-c] pyridine-5-carboxamide: This example is discussed herein It can be prepared according to the coupling procedure.

Example 21 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-c] pyridine-5-carboxamide: This example is discussed herein It can be prepared according to the coupling procedure.

Example 21 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide: couple Yield through the ring was 66%. MS (EI) m / z 287 (M ⁺ ).

Example 21 (vi) : N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-c] pyridine-5-carboxamide: This example is discussed herein According to the coupling procedure.

Example 22 (i) : exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide Fumarate:

Methyl thieno [3,2-c] pyridine-6-carboxylate ( C155 ) (678 mg, 3.5 mmol) was dissolved in MeOH (16 mL) and H ₂ 0 (2 mL). 2M NaOH (1.8 mL, 3.6 mmol) was added dropwise and the solution was stirred at room temperature. After 2 days (ester completely disappeared by TLC), the solution was concentrated in vacuo. The residue was dissolved in H ₂ 0 (12 mL) and the pH was adjusted to 3.5 with 10% HCl. The precipitated solid was filtered off and the solid was rinsed with ether to give thieno [3,2-c] pyridine-6-carboxylic acid ( C160 ) as a white solid (yield 43%). HRMS (FAB) calc'd for C ₈ H ₅ NO ₂ S + H: 180.0119, found 180.0123 (M + H).

Example 22 forms Example 22 (i) by coupling an exo- (4S)-[2.2.1] -3-amine with C160 and then forming a fumarate salt as described in steps 1a and 1b, respectively. Obtained in% yield. MS (ESI) for C ₁₄ H ₁₆ N ₃ SO m / e: 274 (M + H).

Example 22 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide: present The examples can be prepared according to the coupling procedure discussed herein.

Example 22 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide: present The examples can be prepared according to the coupling procedure discussed herein.

Example 22 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-c] pyridine-6-carboxamide: This example is discussed herein It can be prepared according to the coupling procedure.

Example 22 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-6-carboxamide: This example is discussed herein It can be prepared according to the coupling procedure.

Example 22 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide: Example Example 22 (v) can be prepared by coupling C160 with exo- [3.2.1] -amine using the coupling procedure described herein. Yield through the coupling was 58%. MS (EI) m / z 287 (M ⁺ ).

Example 22 (vi) : N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-c] pyridine-6-carboxamide: This example is discussed herein It can be prepared according to the coupling procedure.

Example 23 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide:

2,4-rutidine (51.4 mL, 0.445 mole) was added dropwise under N ₂ to 250 mL of flammable sulfuric acid in a flask in an ice bath. The solution was treated over 15 minutes with potassium nitrate (89.9 g, 0.889 mole). The reaction was stirred for 1 hour in an ice bath and for 2 hours at room temperature, slowly warmed for 5 hours in a 100 ° C. oil bath and then for 4 hours in a 130 ° C. oil bath. The mixture was cooled, poured into 1000 mL of ice and the mixture was neutralized with NaHCO ₃ (1.100 g, 13.1 mole). Precipitated Na ₂ SO ₄ was filtered off, the solid was washed with 500 mL of H ₂ O and the filtrate was extracted with 4 × 500 mL of ether. The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give a yellow oil (50 g). The crude oil was distilled in vacuo to give three fractions: 16 g of recovered 2,4-rutidine (85 ° C.), 2 contaminated with 25% 2,4-dimethyl-5-nitropyridine (135-145 ° C.) 16 g of, 4-dimethyl-3-nitro-pyridine ( C169 ), and 2,4-dimethyl-5-nitro-pyridine ( C170 ) contaminated with 2,4-dimethyl-3-nitropyridine (145 to 153 ° C) 16 g. ¹ H NMR (CDCl ₃₎ of C169 δ2.33, 2.54, 7.10, 8.43 ppm. Of _{^{C170 1 HNMR (CDCl 3) δ2.61}} , 2.62, 7.16, 9.05 ppm.

C170 / C169 (75:25) (5.64 g, 37 mmol) was combined with benzeneselenic anhydride (8.2 g, 22.8 mmol) in 300 mL dioxane in a flask under N ₂ . The reaction was warmed to reflux for 10 hours, cooled and concentrated to yield a black yellow oil. The oil was chromatographed through 250 g of silica gel (230-400 mesh) eluting with 15% EtOAc / hexanes to give 2-formyl-4-methyl-5-nitropyridine ( C171 ) (yield 66%). HRMS (EI) calcd for C ₇ H ₆ N ₂ 0 ₃ : 166.0378, found 166.0383 (M ⁺ ).

C171 (1.15 g, 6.9 mmol), p-toluene sulfonic acid (41 mg, 0.22 mmol) and ethylene glycol (1.41 mL, 25 mmol) were added to 25 mL of toluene in a flask equipped with a Dean-Stark trap. The reaction was warmed to reflux for 2 hours, cooled to room temperature and concentrated in vacuo to give an oil residue. Crude oil was chromatographed through 40 g of silica gel (Biotage) eluting with 20% EtOAc / hexanes to give 2- (1,3-dioxolan-2-yl) -4-methyl-5-nitropyridine ( C172 ) ( Yield 90%) was obtained. MS (EI) for C ₉ H ₁₀ N ₂ 0 ₄ , m / z: 210 (M) ⁺ .

C172 (1.3 g, 6.2 mmol) and DMF dimethyl acetal (1.12 mL, 8.4 mmol) were added to 15 mL of DMF under N ₂ . The reaction was warmed to 90 ° C. for 3 hours, cooled and the reaction concentrated in vacuo. The residue was combined with 1.25 g of 5% Pd / BaSO _{4 in} 20 mL of EtOH in a 250 mL Parr shaker and the mixture was hydrogenated at ambient pressure until absorption stopped. The catalyst was filtered off and the filtrate was combined with 500 mg of 10% Pd / C catalyst in a 250 mL Parr shake bottle. The mixture was hydrogenated at ambient pressure for 1 hour. Hydrogen absorption was no longer observed. The catalyst was filtered off and the filtrate was concentrated in vacuo to give a tan solid. The crude material was chromatographed through 50 g of silica gel (230-400 mesh) eluting with 7% MeOH / CH ₂ Cl ₂ . Appropriate fractions were combined and concentrated to give 5- (1,3-dioxolan-2-yl) -1H-pyrrolo [2,3-c] pyridine ( C173 ) (yield 69%). MS for C ₁₀ H ₁₀ N ₂ 0 ₂ , (EI) m / z: 190 (M) ⁺ .

C173 (800 mg, 4.21 mmol) was dissolved in 44 mL of 10% aqueous acetonitrile. p-toluene sulfonic acid (630 mg, 3.3 mmol) was added and the mixture was heated to reflux for 5 hours. The mixture was cooled to rt, concentrated in vacuo and the resulting residue diluted with 15 mL of saturated NaHCO ₃ . The light yellow solid was collected, washed with water and dried to give 1 H-pyrrolo [2,3-c] pyridine-5-carbaldehyde ( C174 ) (yield 81%). HRMS (FAB) calc'd for C ₈ H ₆ N ₂ O + H: 147.0558, found 147.0564 (M + H).

C174 (500 mg, 3.42 mmol) was dissolved in 1.5 mL of formic acid. The solution was cooled in an ice bath, 30% aqueous hydrogen peroxide (722 μl, 6.8 mmol) was added dropwise and the reaction was stirred in an ice bath for 1 hour and left at 5 ° C. overnight. The mixture was diluted with H ₂ O, the solid collected, washed with H ₂ 0 and dried to give 522 mg of off-white solid. The formate salt was added to 7 mL of H ₂ O, 3 mL of 2N NaOH, and the pH was adjusted to 3 with 5% aqueous HCl. The precipitate was collected and dried to give 1H-pyrrolo [2,3-c] pyridine-5-carboxylic acid ( C176 ) (yield 67%). HRMS (FAB) calc'd for C ₈ H ₆ N ₂ 0 ₂ + H: 163.0508, found 163.0507 (M + H).

Example 23 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C176 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 23 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide .

Example 23 (ii) N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -1H-pyrrolo [2,3c] pyridine-5-carboxamide.

Example 23 (iii) : N- (2-azabicyclo [2.2.1] -hept-5-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide.

Example 23 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide.

Example 23 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide .

Example 23 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide.

Example 24 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide:

5- (1,3-dioxolan-2-yl) -1H-pyrrolo [2,3-c] pyridine ( Cl73 ) (1.05 g, 5.52 mmol) was dissolved in 20 mL THF in a dry flask under N _2. . 60% sodium hydride (243 mg, 6.07 mmol) was added and the reaction stirred for 30 minutes, methyl iodide (360 μl, 5.8 mmol) was added and the reaction stirred at rt overnight. The reaction was concentrated in vacuo and the residue was partitioned between 10 mL saturated NaCl and CH ₂ Cl ₂ (4 × 10 mL). The combined organic layers were dried over anhydrous K ₂ CO ₃ and concentrated in vacuo to give a brown paste. The crude material was chromatographed with silica gel (230-400 mesh) eluting with 5% MeOH / CH ₂ Cl ₂ . Appropriate fractions were combined and concentrated to give 5- (1,3-dioxolan-2-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine ( C175 ) (yield 86%). HRMS (FAB) calc'd for C ₁₁ H ₁₂ N ₂ 0 ₂ + H: 205.0977, found 205.0983.

C175 (920 mg, 4.5 mmol) was dissolved in 25 mL of 10% aqueous acetonitrile in a flask. p-toluene sulfonic acid (630 mg, 3.3 mmol) was added and the mixture was heated to 90 ° C. for 8 h. The mixture was cooled to rt, concentrated in vacuo and the residue partitioned between 15 mL of saturated NaHCO ₃ and CH ₂ Cl ₂ (4 × 10 mL). The combined organic layers were dried over anhydrous K ₂ CO ₃ and concentrated in vacuo to afford 1-methyl-pyrrolo [2,3-c] pyridine-5-carbaldehyde ( C177 ) (yield 99%). HRMS (FAB) calc'd for C ₉ H ₈ N ₂ O + H: 161.0715, found 161.0711.

C177 (690 mg, 4.3 mmol) was dissolved in 2 mL of formic acid. The solution was cooled in an ice bath, 30% aqueous hydrogen peroxide (970 μl, 8.6 mmol) was added dropwise and the reaction was stirred in an ice bath for 1 hour and left at 5 ° C. overnight. The mixture was concentrated to dryness, suspended in H ₂ O and the pH adjusted to 7 with 2N NaOH. The mixture was concentrated to dryness, dissolved in MeOH and passed through 15 mL of 50 W-X2 ion exchange resin (in hydrogen form) eluting with 200 mL of MeOH followed by 200 mL of 5% Et ₃ N / MeOH. The basic wash was concentrated to dryness to give 1-methyl-pyrrolo [2,3-c] pyridine-5-carboxylic acid ( C178 ) (yield 78%). HRMS (FAB) calc'd for C ₉ H ₈ N ₂ 0 ₂ + H: 177.0664, found 177.0672 (M + H).

Example 24 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C178 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 24 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5 Carboxamide.

Example 24 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5 Carboxamide.

Example 24 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide.

Example 24 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide.

Example 24 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5 Carboxamide.

Example 25 (i) : N- (exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl) -3-bromofuro [2,3-c] pyridine-5-carbox Amide 1.5 Fumarate

Furo [2,3-c] pyridin-5-ylmethyl acetate (5.17 g, 27.05 mmol) is dissolved in CH ₂ Cl ₂ (130 mL), layered with saturated NaHCO ₃ (220 mL), Br ₂ (8.36 mL, 162.3 mmol) and stirred very slowly at rt for 4.5 h. The mixture was stirred vigorously for 30 minutes, diluted with CH ₂ Cl ₂ (100 mL) and the layers separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 100 mL) and the combined organic layers were concentrated to a small volume under a stream of nitrogen. The solution was diluted with EtOH (200 mL), treated with K ₂ CO ₃ (22.13 g, 160.1 mmol) and stirred at rt for 2.5 days. The mixture was concentrated to dryness, partitioned between 50% saturated NaCl (200 mL) and CH ₂ Cl ₂ (5 × 200 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to afford a yellow solid (6.07 g). The crude material was adsorbed onto silica gel (12 g) and chromatographed through 250 g of slurry-packed silica gel eluting with a gradient of 100% EtOAc in 50% EtOAc / hexanes. The appropriate fractions were combined and concentrated in vacuo to give 5.02 g (81%) of (3-bromofuro [2,3-c] pyridin-5-yl) methanol as a white solid. MS (EI) m / z: 227 (M ⁺ ).

Oxalyl chloride (1.77 mL, 20.1 mmol) was combined with CH ₂ Cl ₂ (60 mL) in a dried flask under nitrogen, cooled to -78 ° C, treated dropwise with DMSO (2.86 mL, 40.25 mmol), Stir for 20 minutes. The cold solution was treated dropwise with a solution of (3-bromofuro [2,3-c] pyridin-5-yl) methanol (4.0 mg, 17.5 mmol) in THF (50 mL), stirred for 1 hour and then Treated with Et ₃ N (12.2 mL, 87. 5 mmol) dropwise. The mixture was stirred at -78 ° C for 30 minutes and then at 0 ° C for 30 minutes. The mixture was washed with saturated NaHCO ₃ (120 mL), the organic layer was dried over K ₂ CO ₃ and concentrated in vacuo to give a black yellow solid (3.91 g). The crude material was chromatographed with 150 g of slurry-pack silica gel eluting with 30% EtOAc / hexanes. The appropriate fractions were combined and concentrated in vacuo to give 3.93 g (99%) of 3-bromofuro [2,3-c] pyridine-5-carbaldehyde as a white solid. MS (EI) m / z: 225 (M ⁺ ).

3-bromofuro [2,3-c] pyridine-5-carbaldehyde (3.26 g, 14.42 mmol) was dissolved in THF (100 mL) / t-BuOH (50 mL) / H ₂ 0 (50 mL). And treated once with NaOCl ₂ (4.89 g, 43.3 mmol) and KH ₂ PO ₄ (3.92 g, 28.8 mmol) and stirred at rt for 18 h. The white solid was collected via filtration and the filtrate was concentrated to dryness in vacuo. The residue was suspended in water (25 mL), acidified to pH 2 with concentrated HCl, and the resulting solid collected through filtration. The collected solids were dried in a vacuum oven at 50 ° C. for 18 hours and combined to give 3.52 g (99%) of 3-bromofuro [2,3-c] pyridine-5-carboxylic acid as a white solid. MS (EI) m / z: 241 (M ⁺ ).

DIEA (400 μl, 2.30 mmol) and exo-4 (S) were added to a stirred suspension of 3-bromofuro [2,3-c] pyridine-5-carboxylic acid (182 mg, 0.75 mmol) in DMF (10 mL). )-[2.2.1] -3-amine (343 mg, 0.75 mmol) was added. The mixture was cooled to 0 ° C. in an ice bath and HATU (286 mg, 0.75 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue partitioned between saturated aqueous K ₂ CO ₃ solution and chloroformmethanol (95: 5). The aqueous layer was extracted with chloroform (3X). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 50 mg (20%) of amide as a white solid.

To a stirred solution of the amide (50 mg, 0.15 mmol) in MeOH (5 mL) was added a solution of fumaric acid (66 mg, 0.35 mmol) in MeOH (5 mL). The solvent was removed in vacuo and the residue was diluted with acetone (5 mL). The mixture was stirred at rt overnight. The solid precipitate was collected by filtration, washed with ether and dried in vacuo overnight to give 53 mg (70%) of Example 25 (i) as a white solid: ¹ H NMR (400 MHz, CD ₃ 0D) δ8.97 , 8.36, 8.31, 6.72, 4.35, 4.34, 3.78-3.72, 3.55-3.36, 3.28-3.25, 3.09, 2.25-2.17, 1.92-1.85.

The following examples can be prepared according to the coupling procedure discussed herein:

Example 25 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-bromofuro [2,3-c] pyridine-5-carbox amides.

Example 25 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-bromofuro [2,3-c] pyridine-5-carbox amides.

Example 25 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide.

Example 25 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide.

Example 25 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-bromofuro [2,3-c] pyridine-5-carbox amides.

Example 26 (i) : N- [exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl] -3-chlorofuro [2,3-c] pyridine-5-carboxamide Fumarate:

Furo [2,3-c] pyridin-5-ylmethanol (7.70 g, 51.63 mmol) is dissolved in pyridine (45 mL), treated with acetic anhydride (14.36 mL, 154.9 mmol) and stirred at room temperature for 18 hours. It was. Pyridine is removed in vacuo, the resulting residue is dissolved in EtOAc (200 mL), washed with 50% saturated sodium bicarbonate (4 × 90 mL), dried over MgSO ₄ and concentrated in vacuo to puro [2, 3-c] pyridine-5-ylmethyl acetate 9.32 g (94%) was obtained as a yellow oil. MS (EI) m / z: 191 (M ⁺ ), 277, 148, 119, 118, 86, 84, 77, 63, 51, 50.

Furo [2,3-c] pyridin-5-ylmethyl acetate (956 mg, 5 mmol) was dissolved in CH ₂ Cl ₂ (40 mL) and cooled to 0 ° C. Chlorine gas was bubbled into the solution for 15 minutes, the cooling bath was immediately removed and the mixture was stirred for 2 hours. The mixture was recooled to 0 ° C., saturated with chlorine gas, the cooling bath was removed and the solution warmed to room temperature. The solution was layered with saturated NaHCO ₃ (20 mL), stirred gently for 2 hours and then vigorously stirred for 15 minutes. The mixture was diluted with saturated NaHCO ₃ (50 mL), extracted with CH ₂ Cl ₂ (1 × 40 mL followed by 1 × 20 mL), dried over K ₂ CO ₃ and concentrated to a volume of 20 mL under a stream of nitrogen. . The solution was diluted with EtOH (35 mL), treated with K ₂ CO ₃ (4.09 g, 29.6 mmol) and stirred at rt for 18 h. Water (7 mL) was added and the mixture was stirred for 2 days. The mixture was concentrated to dryness, partitioned between 50% saturated NaCl (50 mL) and CH ₂ Cl ₂ (4 × 50 mL), dried over K ₂ CO ₃ and concentrated in vacuo to give a brown solid (833 mg). The crude material was chromatographed through 40 g of a baotage column eluting with 50% EtOAc / hexanes. The appropriate fractions were combined and concentrated to give 624 mg (68%) of (3-chlorofuro [2,3-c] pyridin-5-yl) methanol as a yellow oil. ¹ H NMR (DMSO-d ₆ ): δ 4.69, 5.56, 7.69, 8.55, 8.93 ppm.

Oxalyl chloride (231 μl, 2.6 mmol) was combined with CH ₂ Cl ₂ (10 mL), cooled to −78 ° C., treated dropwise with DMSO (373 μl, 5.3 mmol) and stirred for 20 minutes. The cold solution was treated by dropwise addition of a solution of (3-chlorofuro [2,3-c] pyridin-5-yl) methanol (420 mg, 2.3 mmol) in THF (5 mL) / CH ₂ Cl ₂ (5 mL). And stirred for 1 hour and then treated dropwise with Et ₃ N (1.59 mL, 11.45 mmol). The mixture was stirred at -78 ° C for 30 minutes and then at 0 ° C for 30 minutes. The mixture was washed with saturated NaHCO ₃ (20 mL), the organic layer was dried over K ₂ CO ₃ and concentrated in vacuo to give a yellow solid (410 mg). The crude material was chromatographed through 20 g of slurry-pack silica gel eluting with 15% EtOAc / hexanes. The appropriate fractions were combined and concentrated in vacuo to give 322 mg (77%) of 3-chlorofuro [2,3-c] pyridine-5-carbaldehyde as a white solid. ¹ H NMR (CDCl ₃ ): δ 7.89, 8.33, 9.02, 10.18 ppm.

3-chlorofuro [2,3-c] pyridine-5-carbaldehyde (317 mg, 1.74 mmol) was dissolved in THF (10 mL) / t-BuOH (5 mL) / H ₂ O (5 mL) Treated with sodium chlorite (592 mg, 5.24 mmol) and KH ₂ PO ₄ (473 mg, 3.48 mmol) in one portion and stirred for 18 hours at room temperature. The reaction mixture was concentrated to dryness in vacuo, suspended in water (10 mL), acidified to pH 3.5 with concentrated HCl and stirred at rt for 2 h. The resulting solid was filtered, washed with water and stirred for 18 hours at 40 ° C. in a vacuum oven to give 364 mg of 3-chlorofuro [2,3-c] pyridine-5-carboxylic acid as a white solid. MS (EI) m / z: 197 (M ⁺ ).

To a stirred solution of 3-chlorofuro [2,3-c] pyridine-5-carboxylic acid (99 mg, 0.5 mmol) in anhydrous DMF (10 mL), DIEA (265 μl, 1.52 mmol) and exo-4 (S )-[2.2.1] -3-amine (228 mg, 0.5 mmol) was added. The mixture was cooled to -5 ° C in acetone / ice water bath and HATU (190 mg, 0.5 mmol) was added in one portion. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous K ₂ CO ₃ solution and chloroform. The aqueous layer was extracted with chloroform (2X). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the amide as a white solid (125 mg, 85%).

To a stirred solution of the amide (125 mg, 0.43 mmol) in acetone (5 mL) was added to a warm solution of fumaric acid (49.7 mg, 0.43 mmol) in isopropanol (5 mL). The mixture was warmed to 50 ° C for 10 minutes. The solvent was removed in vacuo and the residue was diluted with acetone (5 mL). The mixture was stirred at rt overnight. The solid was collected by filtration, washed with acetone and dried in high vacuum overnight to give 152 mg (87%) of Example 26 (i) as a white solid: ¹ H NMR (400 MHz, CD ₃ 0D) δ8.98, 8.42, 8.32, 6.71, 4.32-4.29, 3.73-3.68, 3.50-3.35, 3.26-3.20, 3.07, 2.22-2.13, 1.89-1.81.

The following examples can be prepared according to the coupling procedure discussed herein:

Example 26 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide .

Example 26 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide .

Example 26 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide.

Example 26 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide.

Example 26 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide .

Example 27 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide:

N-butyl lithium (150.6 ml, 241 mmol) was added dropwise to ether (100 ml) at −20 ° C. under N ₂ . 3-bromothianaphthene (10.5 ml, 80.3 mmol) was dissolved in ether (50 ml) and added dropwise to the cooling solution with stirring of the cooling solution for 0.5 hour. DMF (16.3 ml, 210 mmol) was dissolved in ether (75 ml) and added dropwise, and the solution was further stirred at −20 ° C. for 15 h. The reaction was quenched with ice (300 g) in 10% H ₂ SO ₄ (200 ml) and stirred until both layers turned yellow. The resulting slurry was filtered and the cake was dried in an air stream to give 1-benzothiophene-2,3-dicarbaldehyde ( C180 ) as a yellow solid (yield 60%). HRMS (FAB) calc'd for C ₁₀ H ₆ 0 ₂ S + H: 191.0167, found 191.0172 (M + H).

1-benzothiophene-2,3-dicarbaldehyde ( C180 ) (1.91 g, 10.0 mmol) was dissolved in CH ₂ Cl ₂ (100 ml) and cooled in an ice bath. Methyl (acetylamino) (dimethoxyphosphoryl) acetate ( C152 ) (2.63 g, 11.0 mmol) is dissolved in CH ₂ Cl ₂ (50 ml) and 1,8-diazabicyclo [5.4.0] un-7-7 -En (1.65 ml, 11.0 mmol) was added and stirred for 5 minutes. This solution was added dropwise to the cooled thiophene solution. The reaction mixture was stirred in an ice bath for 1 hour and then at room temperature overnight. The reaction was concentrated in vacuo and the crude was chromatographed through 500 g of slurry-pack silica eluting with 50% ethyl acetate / hexanes to methyl benzothieno [3,2-c] pyridine-3-carboxylate ( C181 ) Was obtained as a white solid (yield 73%). MS for C ₁₃ H ₉ NO ₂ S, (EI) m / z: 243 (M) ⁺ .

C181 (1.43 g, 5.87 mmol) was dissolved in MeOH (25 ml) containing H ₂ 0 (3 ml). 2M NaOH (3.0 ml, 6.0 mmol) was added dropwise and the solution was stirred at room temperature. After 4 days (ester completely disappeared by TLC), the reaction was concentrated in vacuo. The residue was dissolved in H ₂ 0 (5 ml) and the pH was adjusted to 3 with 10% HCl. After the solution was stirred overnight the precipitation was complete. The slurry was filtered and the cake was rinsed with ether to give benzothieno [3,2-c] pyridine-3-carboxylic acid ( C182 ) as a white solid in 100% yield. HRMS (FAB) calc'd for C ₁₂ H ₇ NO ₂ S + H, 230.0276. Found 230.0275 (M + H).

Example 27 (i) can be obtained by coupling exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine with C182 .

The following examples can be prepared according to the coupling procedure discussed herein:

Example 27 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide.

Example 27 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide.

Example 27 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) -benzothieno [3,2-c] pyridine-3-carboxamide.

Example 27 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) -benzothieno [3,2-c] pyridine-3-carboxamide.

Example 27 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide.

Example 27 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide.

Example 28 (i) : N- (1-azabicyclo [2.2.1] hept-3-yl) thieno [3,4-c] pyridine-6-carboxamide:

3,4-Dibromothiophene (12.5 ml, 113 mmol) was combined with CuCN (30.4 g, 339 mmol) in DMF (40 ml) in a dry flask under nitrogen using an over-head stirrer. The reaction was refluxed at 180 ° C. for 5 hours. The black mixture was then poured into a solution of FeCl ₃ (113.6 g, 700 mmol) in 1.7 M HCl (200 ml) and again heated at 65 ° C. for 0.5 h using an overhead-head stirrer. The reaction was cooled to rt and extracted with CH ₂ Cl ₂ (7 × 300 ml). Each extract was washed with 6M HCl (2X), water, saturated NaHCO ₃ and 200 mL each. The organic layers were then combined, dried over MgSO ₄ , filtered and concentrated to give 10.49 g (69%) of 3,4-dicyanothiophene as a downy tan solid. HRMS (EI) calc'd for C ₆ H ₂ N ₂ S: 133.9939, found 133.9929 (M ⁺ ).

3,4-dicyanothiophene (5.0 g, 37.2 mmol) was suspended in benzene (150 ml) in a dry flask under nitrogen using an overhead head stirrer. Diisobutyl aluminum hydride (1.OM in toluene) (82.0 ml, 82.0 mmol) was added dropwise and the reaction was stirred at rt for 2 h. The reaction was then quenched carefully with MeOH (5 ml) and poured into 30% H ₂ SO ₄ (60 ml) containing ice (200 g). The slurry was stirred and all the layers separated until all the mass had dissolved. The aqueous layer was extracted with Et ₂ O (4 × 200 ml) and the combined organic layers were dried over MgSO ₄ , filtered and adsorbed onto silica. The crude material was chromatographed through 225 g of slurry-packed silica eluting with 40% EtOAc / hexanes. The appropriate fractions were combined and concentrated to give 1.88 g (36%) of 3,4-thiophene dicarboxaldehyde as a pale yellow solid. MS (EI) m / z: 140 (M ⁺ ).

3,4-thiophene dicarboxaldehyde (1.0 g, 7.13 mmol) was dissolved in CH ₂ Cl ₂ (40 ml) and cooled to 0 ° C. Methyl (acetylamino) (dimethoxyphosphoryl) acetate (1.88 g, 7.85 mmol) was dissolved in CH ₂ Cl ₂ (30 ml) and combined with DBU (1.1 ml, 7.85 mmol). The solution was stirred for 5 minutes and then added dropwise to the cooled thiophene solution. The reaction mixture was stirred for 1 hour at 0 ° C. and then overnight at room temperature. The volatiles were removed in vacuo and the crude material was chromatographed through 68 g of slurry-pack silica eluting with 70% EtOAc / hexanes. Suitable fractions were combined and concentrated to give 2.09 g of carbinol intermediate as a white foam. The intermediate was dissolved in CHCl ₃ (50 ml) and treated dropwise with DBU (1.32 ml, 8.8 mmol) and trifluoroacetic anhydride (1.24 ml, 8.8 mmol). The reaction was stirred at rt overnight then quenched with saturated NaHC0 ₃ solution (50 ml). The layers were separated and the aqueous layer was extracted with CHCl ₃ (2 × 50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a yellow oil. This oil was chromatographed through 50 g of slurry-packed silica eluting with 90% EtOAc / hexanes. The appropriate fractions were combined and concentrated to give 1.2 g (88%) of methyl thieno [3,4-c] pyridine-6-carboxylate as a yellow solid. MS (EI) m / z: 193 (M ⁺ ).

Methyl thieno [3,4-c] pyridine-6-carboxylate (250 mg, 1.3 mmol) was dissolved in MeOH (7 ml) and water (1 ml). 2M NaOH (0.72 ml, 1.43 mmol) was added dropwise. The reaction was stirred at rt overnight and monitored by TLC. The volatiles were removed in vacuo and the residue was dissolved in water (2 ml). The pH was adjusted to 3 with 10% HCl and the reaction was again stirred at rt overnight. The aqueous solution was extracted repeatedly with EtOAc (20 x 10 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a yellow solid. The amount of product isolated through extraction was minimized (67 mg) to concentrate the aqueous layer, and the aqueous layer was found to contain most of the product. The solid aqueous residue was extracted with EtOAc to give 225 mg (97%) of thieno [3,4-c] pyridine-6-carboxylic acid as a yellow solid. MS (EI) m / z: 179 (M ⁺ ).

Example 28 (i) uses exo- [2.2.1] -3-amine or endo- [2.2.1] -3-amine as thieno [3,4-c] pyridine- using the procedure discussed herein. It can be obtained by coupling to 6-carboxylic acid.

The following examples can be prepared according to the coupling procedure discussed herein:

Example 28 (ia) : N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) thieno [3,4-c] pyridine-6-carboxamide.

Example 28 (ii) : N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) thieno [3,4-c] pyridine-6-carboxamide.

Example 28 (iii) : N- (2-azabicyclo [2.2.1] hept-5-yl) thieno [3,4-c] pyridine-6-carboxamide.

Example 28 (iv) : N- (2-azabicyclo [2.2.1] hept-6-yl) thieno [3,4-c] pyridine-6-carboxamide.

Example 28 (v) : N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,4-c] pyridine-6-carboxamide.

Example 28 (vi) N- (1-azabicyclo [3.2.2] non-3-yl) thieno [3,4-c] pyridine-6-carboxamide.

Materials and Methods for Measuring α7 nAChR Agonist Activity

EC of α7 nAChR agonist ₅₀ -Based analysis to measure

α7-5HT ₃ Constitution and Expression of Receptors:

Eisele JL, et al., Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities, Nature (1993), Dec. 2; 366 (6454): 479-83 and modified by Groppi, et al., WO 00/73431, wherein the N-terminal 201 amino acid is extracted from human α7 nAChR containing the ligand binding domain of the ion channel. The encoding cDNA was fused to the cDNA encoding the pore forming region of the mouse 5HT ₃ receptor. Chimeric α7-5HT ₃ ion channels were incorporated into pGS175 and pGS179 containing resistance genes for G-418 and hygromycin B, respectively. Both plasmids were simultaneously infected with SHEP1 cells and cell lines resistant to both G-418 and hygromycin B were selected. Cell lines expressing chimeric ion channels were identified by the cell line's ability to bind fluorescent α-bungarus toxin on the cell surface. Cells with the highest amount of fluorescent α-bungarus toxin binding were isolated using a fluorescent active cell sorter (FACS). 10% fetal albumin, L-glutamine, penicillin / streptomycin 100 units / ml, fungizone 250 ng / in continuous culture for at least 4 weeks in standard mammalian cell incubator at 6% CO ₂ and 37 ° C. After growing cells in minimal essential medium that does not contain essential amino acids supplemented with mg, 400 μg / ml of hygromycin B and 400 μg / ml of G-418, the chimeric α7- by measuring the fluorescent α-bungarus toxin binding Cell lines stably expressing 5HT ₃ were identified.

Chimera α7-5HT ₃ Analysis of receptor activity

To analyze the activity of the α7-5HT ₃ ion channel, cells expressing the channel were plated and grown in each well of 96 or 384 well dishes (Corning # 3614) and joined prior to analysis. On the day of analysis, a 1: 1 mixture of 2 mM calcium green 1, AM (micro probe) and 20% Pluronic F-127 (micro probe) dissolved in anhydrous DMSO was loaded. This solution was added directly to the growth medium of each well to achieve a final concentration of 2 μΜ. Cells were incubated with dye at 37 ° C. for 60 minutes and then washed with Earle Balanced Salt Solution (MMEBSS) in modified form as described in WO 00/73431. The ion concentration of MMEBSS was adjusted as described in WO 00/73431 to maximize the flow of calcium ions through the chimeric α7-5HT ₃ ion channel. The activity of the compounds in the chimeric α7-5HT ₃ ion channel was analyzed on FLIPR. The device was installed with an excitation wavelength of 488 nanometers using 500 milliwatts of power. Fluorescence emission was measured at 525 nanometers or more with a suitable F-stop to maintain the maximum signal: noise ratio. Agonist activity measurement of each compound was performed by adding the compound directly to cells expressing the chimeric α7-5HT ₃ ion channel and measuring intracellular calcium increase by agonist-induced activation of the chimeric ion channel. The assay was quantified so that the concentration-dependent increase in intracellular calcium was measured as the concentration-dependent change in calcium green fluorescence. The effective concentration of the compound required to produce 50% of the maximum increase in intracellular calcium is EC ₅₀ . The following examples were tested to obtain EC ₅₀ values from about 40 nM to about 1200 nM: Example 1 (i), Example 1 (ib), Example 1 (id), Example 1 (v), Example Example 1 (vi), Example 2 (v), Example 7 (i), Example 7 (v), Example 8 (i), Example 11 (i), Example 21 (i), Example 21 (v), Example 22 (i), Example 22 (v), Example 25 (i) and Example 26 (i).

Coupling Constants:

Another method of measuring the α7 nAChR agonist activity is to determine the binding constant of the potential agonist in a competitive binding assay. For the α7 nAChR agonist, there was a good correlation between the functional EC ₅₀ value using the chimeric α7-5HT ₃ ion channel as the drug target and the binding activity of the compound to endogenous α7 nAChR.

Membrane manufacturing

Spragu-Dully male rats (300-350 g) were sacrificed with the head, and the brain (except the cerebellum in the whole brain) was quickly incised, weighed, and the rotating pestle set at 50 (stroke 10) Homogenized at 9 volumes / wet weight g of ice cold 0.32 M sucrose. Homogenates were centrifuged at 1,000 xg for 10 minutes at 4 ° C. Supernatants were collected and centrifuged at 20,000 × g for 20 minutes at 4 ° C. The resulting pellet was resuspended to a protein concentration of 1-8 mg / mL. Aliquots of 5 mL homogenate were frozen at -80 ° C until needed for analysis. On the day of the assay, aliquots were thawed at room temperature and pH containing Kreb-4.16 mM NaHC0 ₃ , 0.44 mM KH ₂ PO ₄ , 127 mM NaCl, 5.36 mM KCl, 1.26 mM CaCl ₂ and 0.98 mM MgCl ₂ . Diluted with 20 mM Hepes buffer at 7.0 (at room temperature), added 25-150 μg of protein per test tube. Bradford method using bovine serum albumin as a reference [Bradford, MM, Anal. Biochem., 72,248-254, 1976].

Binding analysis .

For saturation studies, 0.4 mL of homogenate was added to a test tube containing buffer and various concentrations of radioligand and incubated for 1 hour at 25 ° C. with a final volume of 0.5 mL. Nonspecific binding was measured in tissues incubated simultaneously in the presence of 0.05 ml of MLA with a final concentration of 1 μM added prior to radioligand. In a competitive study, drugs were added to test tubes with increasing concentrations prior to addition of 0.05 mls of [ ³ H] -MLA for final concentrations between 3.0 and 4.0 μM. Incubation was terminated by rapid vacuum filtration through Whatman GF / B glass filter paper mounted on a 48 well Brandel cell harvester. The filter was presoaked in 50 mM Tris HCl-0.05% polyethyleneimine at pH 7.0. The filter was quickly washed twice with 5 mL of chilled 0.9% brine aliquot and then counted for radioactivity by a liquid scintillation counter.

Data analysis .

In a competitive binding study, Cheng-Prusoff expression [Cheng, YC and Prossoff, WH, Biochem. Pharmacol., 22, p. 3099-3108,1973] the inhibition constant (Ki) was calculated from the concentration dependent inhibition of [ ³ H] -MLA binding obtained from a nonlinear regression fit program. Hill constants were obtained using non-linear regression (GraphPad Prism sigmoidal dose-response with variable slope).

Claims (60)

A compound of formula (I) or a pharmaceutically acceptable salt, racemic mixture, and pure enantiomers thereof: <Formula 1> Wherein azabicyclo is ego, W is This, Provided that the bond between the —C (═X) —group and the W group can be attached to any available carbon atom in the W group as shown in R ₃ , R ₆ and R ₁₅ ; X is O or S; R ₀ is H, lower alkyl, substituted lower alkyl or halogenated lower alkyl; Each R ₁ is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl or substituted naphthyl; Each R ₂ is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, aryl, F, Cl, Br, I or R ₂ is absent when k ₂ , k ₅ or k ₆ is 0; R _2-3 is H, alkyl, substituted alkyl, halogenated alkyl, F, Cl, Br or I; k ₂ is 0 or 1; k ₅ and k ₆ are independently 0, 1 or 2; A --- A '--- A "is N (R ₄ ) -C (R ₃ ) = C (R ₃ ), N = C (R ₃ ) -C (R ₁₅ ) ₂ , C (R ₃ ) = C (R ₃ ) -N (R ₄ ), C (R ₃ ) ₂ -N (R ₄ ) -C (R ₃ ) ₂ , C (R ₁₅ ) ₂ -C (R ₃ ) = N, N ( R ₄ ) -C (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -C (R ₃ ) ₂ -N (R ₄ ), OC (R ₃ ) = C (R ₃ ), OC (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -OC (R ₃ ) ₂ , C (R ₃ ) = C (R ₃ ) -O, C (R ₃ ) ₂ -C (R ₃ ) ₂ -O, SC (R ₃ ) = C (R ₃ ), SC (R ₃ ) ₂ -C (R ₃ ) ₂ , C (R ₃ ) ₂ -SC (R ₃ ) ₂ , C ( R ₃ ) = C (R ₃ ) -S or C (R ₃ ) ₂ -C (R ₃ ) ₂ -S; Each R ₃ is independently a bond with the core molecule, provided that only R ₃ is the bond and R ₆ or R ₁₅ is not such a bond, H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted Alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, -CN, -N0 ₂ , F, Br, Cl, I, -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -S (O) ₂ R ₁₉ , -C (O) R ₁₉ , -CO ₂ R ₁₉ , aryl, R ₇ or R ₉ ; J, L, M and Q are N or C (R ₆ ), provided that only one of J, L, M or Q is N and the rest are C (R ₆ ), and further that the core molecule is a When attached to the denyl moiety Q is C (H) and additionally there is only one attachment to the core molecule; G and Y are C (R ₆ ), provided that when the molecule is attached to the phenyl moiety in Y, G is CH; R ₄ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R ₇ or R ₉ ; Each R ₅ is independently H, lower alkyl or lower alkenyl; Each R ₆ is independently H, F, Br, I, Cl, -CN, -CF ₃ , -OR ₅ , -SR ₅ , -N (R ₅ ) ₂ or a bond to a core molecule, provided that only R ₆ Only one is said bond and R ₃ or R ₁₅ is not said bond); V is selected from O, S or N (R ₄ ); R ₇ contains 1 to 3 heteroatoms independently selected from the group consisting of = N—, —N (R ₁₇ ) —, —O— and —S— in the ring, 0 to 1 substituents selected from R ₁₈ Is a 5-membered heteroaromatic mono-cyclic moiety having 0 to 3 substituents independently selected from F, Cl, Br or I, or R ₇ is a 5-membered ring having the formula A 9-membered fused ring moiety having a fused 6-membered ring: Wherein, G ₁ is O, S or NR ₁₇ , Wherein G is C (R ₁₆ ) or N, each G ₂ and G ₃ is independently selected from C (R ₁₆ ) ₂ , C (R ₁₆ ), O, S, N and N (R ₁₈ ) Provided that G ₂ and G ₃ are both O at the same time, S at the same time, or not O and S at the same time, Wherein G is C (R ₁₆ ) or N, and each G ₂ and G ₃ are independently selected from C (R ₁₆ ) ₂ , C (R ₁₆ ), O, S, N and N (R ₁₇ ) , Each 9-membered fused ring moiety bears 0 to 1 substituents selected from R ₁₈ and further carries 0 to 3 substituent (s) independently selected from F, Cl, Br or I, wherein R _{The 7} moiety is attached to another substituent as defined in Formula (I) as valency is allowed at any position on any ring; Each R ₈ is independently H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R ₇ , R ₉ , Phenyl or substituted phenyl; R ₉ contains 1 to 3 heteroatoms selected from = N- in the ring, 0 to 1 substituents selected from R ₁₈ and 0 to 3 substituent (s) independently selected from F, Cl, Br or I Or a ₉ -membered heteroaromatic mono-cyclic moiety having 1 to 3 heteros selected from = N-, including but not limited to, quinolinyl or isoquinolinyl in one or all two rings A 10-membered heteroaromatic acyclic portion containing an atom, wherein each 10-membered fused ring portion is 0 to 1 substituents selected from R ₁₈ and 0 independently selected from F, Cl, Br or I Has from 3 to 3 substituent (s) and, where valences are acceptable, a bond attached directly or indirectly to the core molecule; Each R ₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl, 1 substituent selected from a cycloalkyl, R ₁₃ is substituted by 1 substituent selected from alkyl, R ₁₃ is substituted by 1 substituent selected from R ₁₃ Substituted heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl or substituted phenyl; Each R ₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl or halogenated heterocycloalkyl; R ₁₂ is —N0 ₂ , —CN, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ or- NR ₁₁ S (O) ₂ R ₁₁ ; R ₁₃ is -CN, -CF ₃ , -N0 ₂ , -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ or -NR ₁₁ S (O) ₂ R ₁₁ ; Each R ₁₄ is H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, -CN, -NO ₂ , -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -S (O) ₂ R ₁₉ , -C (O) R ₁₉ ,- CO ₂ R ₁₉ , aryl, R ₇ or R ₉ ; Each R ₁₅ is independently alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, F, Br, Cl, I, -CN, -N0 ₂ , -OR ₁₉ , -C (O) N (R ₁₀ ) ₂ , -N (R ₁₀ ) ₂ , -SR ₁₉ , -CO ₂ R ₁₉ , aryl, R ₇ , R ₉ or to the core molecule Only one R ₁₅ is said bond and R ₆ or R ₃ is not said bond; Each R ₁₆ is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, F, Cl, Br, I, -N0 ₂ , -CN, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ , -NR ₁₁ S (0) ₂ R ₁₁ or a bond attached directly or indirectly to a core molecule, provided that the bond to the core molecule in the 9-membered fused ring moiety is Only one, in addition, the fused ring moiety is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -NO ₂ , -C (O) NR ₁₁ R ₁₁ , -CN, -NR ₁₁ C (O) R ₁₁ , -S (O ) ₂ NR ₁₁ R ₁₁ or _{-NR 11 S (O) 2 R} 0 to 1 selected from ₁₁ Which may have a substituent, and have the additional, fused ring part is from 0 to 3 substituents selected from F, Cl, Br or I (s); R ₁₇ has 1 substituent selected from H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, -SO ₂ R ₈ or R _{18 and} is selected from F, Cl, Br or Phenyl further having 0 to 3 substituents independently selected from I; R ₁₈ is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O ) NR ₁₁ R ₁₁ , -CN, -NR ₁₁ C (O) R ₁₁ , -S (O) ₂ NR ₁₁ R ₁₁ , -NR ₁₁ S (O) ₂ R ₁₁ , -NO ₂ , F, Cl, Br , Alkyl substituted with 1 to 4 substituent (s) independently selected from I or R ₁₃ , F, Cl, Br, cycloalkyl substituted with 1 to 4 substituent (s) independently selected from I or R ₁₃ , or Heterocycloalkyl substituted with 1 to 4 substituent (s) independently selected from F, Cl, Br, I or R ₁₃ ; R ₁₉ is H, alkyl, cycloalkyl, substituted alkyl, halogenated alkyl, substituted phenyl or substituted naphthyl. The compound of claim 1, wherein X is O. The compound of claim 2, wherein R ₁ is H, alkyl or cycloalkyl. The compound of claim 3, wherein W is (a). The compound of claim 4, wherein (a) is thieno [2,3-b] pyridin-2-yl, thieno [2,3-b] pyridin-5-yl, thieno [2,3-b] pyridine -6-yl, thieno [3,2-b] pyridin-2-yl, thieno [3,2-b] pyridin-5-yl, thieno [3,2-b] pyridin-6-yl, Thieno [2,3-c] pyridin-2-yl, thieno [2,3-c] pyridin-5-yl, thieno [3,2-c] pyridin-2-yl, thieno [3, 2-c] pyridin-6-yl, furo [3,2-c] pyridin-2-yl, furo [3,2-c] pyridin-6-yl, furo [2,3-b] pyridin-2- 1, furo [2,3-c] pyridin-2-yl, furo [2,3-c] pyridin-5-yl, 2,3-dihydrofuro [2,3-c] pyridin-5-yl or 1H-pyrrolo [2,3-c] pyridin-5-yl, Wherein the compound is selected from F, Br, Cl, I, -CN, -NO ₂ , -CF ₃ , -OR ₅ on up to 4 different carbon atoms, as valency permits and as permitted by the definition of W; , -OR ₁₉ , -SR ₅ , -SR ₁₉ , -N (R ₅ ) ₂ , -N (R ₁₀ ) ₂ , -C (O) R ₁₉ , -CO ₂ R ₁₉ , -C (O) N ( R ₁₀ ) ₂ , -S (O) ₂ R ₁₉ , alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, aryl, R ₇ , optionally substituted with R ₉ , Additionally, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl on nitrogen as permitted by the definition of W, Optionally substituted with R ₇ or R ₉ , However, the compound which couple | bonded W to the core molecule using one carbon. The compound of claim 5, wherein the optional substituents are F, Br, Cl, I, -CN, -CF ₃ , -OR ₅ , -SR ₅ , -N (R ₅ ) ₂ , -C (O) R ₅ ,- CO ₂ R ₅ , -C (O) N (R ₁₀ ) ₂ , -S (O) ₂ R ₅ , lower alkyl, lower substituted alkyl or lower alkynyl, Wherein R ₁₀ is H, lower halogenated alkyl or -CN, -CF ₃ , -NO ₂ , -OR ₁₁ , -SR ₁₁ , -NR ₁₁ R ₁₁ , -C (O) R ₁₁ , -C (O) NR ₁₁ R ₁₁ , -NR ₁₁ C (0) R ₁₁ , -S (0) ₂ NR ₁₁ R ₁₁ or lower alkyl optionally substituted with -NR ₁₁ S (0) ₂ R ₁₁ , wherein R ₁₁ is H, Lower alkyl, lower halogenated alkyl, lower substituted alkyl. The compound of claim 6, wherein the azabicyclo is II, V or VI. 8. The compound of claim 7, wherein each k ₂ , k ₅ and k ₆ are independently 0 or 1. 9. The compound of claim 8, wherein R ₂ is alkyl, halogenated alkyl, substituted alkyl, or R ₂ is absent when k ₂ , k ₅ or k ₆ is zero. The compound of claim 9, wherein R ₂ is absent when R ₁ is H or lower alkyl and R ₂ is lower alkyl or k ₂ , k ₅ or k ₆ is zero. The method of claim 10, Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide; Exo-4 (R) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide; Exo-N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide; (+)-N- [endo-1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-5-carboxamide; (-)-N- [endo-1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-[(exo) -azabicyclo [2.2.1] hept-3-yl] furo [3,2-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) furo [3,2-c] pyridine-6-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carr Boxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; (Exo) -N- [1-azabicyclo [3.2.1] oct-3-yl] -3-methylfuro [2,3-c] pyridine-5-carboxamide; (3R, 5R) -N- [1-azabicyclo [3.2.1] oct-3-yl] -3-methylfuro [2,3-c] pyridine-5-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -furo [2,3-b] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -furo [2,3-b] pyridine-2-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -furo [2,3-b] pyridine-2-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -furo [2,3-b] pyridine-2-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-2-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-b] pyridine-2-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-2-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-b] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-2-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-c] pyridine-2-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-c] pyridine-2-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-2-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-2-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-2-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide; N- [exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl] -3-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; Or a pharmaceutically acceptable salt, pure enantiomer or racemic mixture thereof. The method of claim 11, Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-[(exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl] furo [3,2-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) furo [3,2-c] pyridine-6-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; (Exo) -N- [1-azabicyclo [3.2.1] oct-3-yl] -3-methylfuro [2,3-c] pyridine-5-carboxamide; (3R, 5R) -N- [1-azabicyclo [3.2.1] oct-3-yl] -3-methylfuro [2,3-c] pyridine-5-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-b] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; Exo-4 (S) -N- (1-azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- [exo- (4S) -1-azabicyclo [2.2.1] hept-3-yl] -3-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; Or a pharmaceutically acceptable salt, racemic mixture or pure enantiomer thereof. The method of claim 10, N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-vinylfuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-ethynylfuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3-hydroxyprop-1-ynyl) furo [3,2-c] pyridine- 6-carboxamide; Methyl 3- (6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [3,2-c] pyridin-2-yl) prop 2-inoate; 2- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [3,2-c ] Pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-cyanofuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-chlorofuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-fluorofuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-iodofuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylthio) furo [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylamino) furo [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (formylamino) furo [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- [formyl (methyl) amino] furo [3,2-c] pyridine-6-carbox amides; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-[(trifluoroacetyl) amino] furo [3,2-c] pyridine-6-carbox Boxamide; N-6- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-formylfuro [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (trifluoroacetyl) furo [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylsulfonyl) furo [3,2-c] pyridine-6-carboxamide; Methyl 6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [3,2-c] pyridine-2-carboxylate; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-vinylthieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-ethynylthieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-prop-1-ynylthieno [3,2-c] pyridine-6-carboxamide ; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3-hydroxyprop-1-ynyl) thieno [3,2-c] pyridine -6-carboxamide; Methyl 3- (6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [3,2-c] pyridin-2-yl) prop P-2-inoate; 2- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [3,2- c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-cyanothieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-chlorothieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-fluorothieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-iodothieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-trifluoromethylthieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylthio) thieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylamino) thieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (formylamino) thieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- [formyl (methyl) amino] thieno [3,2-c] pyridine-6-carbox Boxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-[(trifluoroacetyl) amino] thieno [3,2-c] pyridine-6- Carboxamides; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (cyclopropylamino) thieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- [dimethylamino] thieno [3,2-c] pyridine-6-carboxamide; N-6- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [3,2-c] pyridine-2,6-dicarboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2-formylthieno [3,2-c] pyridine-6-carboxamide; 2-acetyl-N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [3,2-c] pyridine-6-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (trifluoroacetyl) thieno [3,2-c] pyridine-6-carboxamide ; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (methylsulfonyl) thieno [3,2-c] pyridine-6-carboxamide; Methyl 6-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [3,2-c] pyridine-2-carboxylate; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-vinylfuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-ethynylfuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3-hydroxyprop-1-ynyl) furo [2,3-c] pyridine- 5-carboxamide; Methyl 3- (5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [2,3-c] pyridin-3-yl) prop 2-inoate; 3- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c ] Pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-cyanofuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-fluorofuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-iodofuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylthio) furo [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylamino) furo [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (formylamino) furo [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [formyl (methyl) amino] furo [2,3-c] pyridine-5-carbox amides; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-[(trifluoroacetyl) amino] furo [2,3-c] pyridine-5-car Boxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (cyclopropylamino) furo [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide; N-5- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-formylfuro [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (trifluoroacetyl) furo [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylsulfonyl) furo [2,3-c] pyridine-5-carboxamide; Methyl 5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} furo [2,3-c] pyridine-3-carboxylate; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-vinylthieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-ethynylthieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-prop-1-ynylthieno [2,3-c] pyridine-5-carboxamide ; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3-hydroxyprop-1-ynyl) thieno [2,3-c] pyridine -5-carboxamide; Methyl 3- (5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [2,3-c] pyridin-3-yl) prop P-2-inoate; 3- (3-amino-3-oxoprop-1-ynyl) -N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [2,3- c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-cyanothieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-chlorothieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-fluorothieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-iodothieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-trifluoromethylthieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylthio) thieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylamino) thieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (formylamino) thieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [formyl (methyl) amino] thieno [2,3-c] pyridine-5-car Boxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-[(trifluoroacetyl) amino] thieno [2,3-c] pyridine-5- Carboxamides; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (cyclopropylamino) thieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- [dimethylamino] thieno [2,3-c] pyridine-5-carboxamide; N-5- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] thieno [2,3-c] pyridine-3,5-dicarboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3-formylthieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (trifluoroacetyl) thieno [2,3-c] pyridine-5-carboxamide ; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (methylsulfonyl) thieno [2,3-c] pyridine-5-carboxamide; Methyl 5-{[exo-4 (S) -1-azabicyclo [2.2.1] hept-3-ylamino] carbonyl} thieno [2,3-c] pyridine-3-carboxylate; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (phenylethynyl) furo [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3,3-trifluoroprop-1-ynyl) furo [2,3- c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3-difluoroprop-1-ynyl) furo [2,3-c] Pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (phenylethynyl) thieno [2,3-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3,3-trifluoroprop-1-ynyl) thieno [2,3 -c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -3- (3,3-difluoroprop-1-ynyl) thieno [2,3-c ] Pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (phenylethynyl) thieno [3,2-c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3,3,3-trifluoroprop-1-ynyl) thieno [3,2 -c] pyridine-5-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] -2- (3,3-difluoroprop-1-ynyl) thieno [3,2-c ] Pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -2-methyl-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-methyl-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -2-ethyl-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -3-ethyl-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -4-methyl-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methylthio-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methoxy-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-chloro-furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-vinylfuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-ethynylfuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-cyanofuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethynylfuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-cyanofuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-fluorofuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-chlorofuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-bromofuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-iodofuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-mercaptofuro [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylthio) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylamino) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (formylamino) furo [3,2-c] pyridine-6-carboxamide; 2- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide; 2- (acetyl) methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(trifluoroacetyl) amino] furo [3,2-c] pyridine-6-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (benzoylamino) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diethylamino) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diisopropylamino) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-yl) furo [3,2-c] pyridine-6-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-yl) furo [3,2-c] pyridine-6-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-yl) furo [3,2-c] pyridine-6-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-yl) furo [3,2-c] pyridine-6-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (4-methylpiperazin-1-yl) furo [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (cyclopropylamino) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-ylcarbonyl) furo [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-ylcarbonyl) furo [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(4-methylpiperazin-1-yl) carbonyl] furo [3,2-c] Pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-ylcarbonyl) furo [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (aziridin-1-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (azetidin-1-ylcarbonyl) furo [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-formylfuro [3,2-c] pyridine-6-carboxamide; 2-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (trifluoroacetyl) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(phenyl) sulfonyl] furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylsulfonyl) furo [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -4-methyl-thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methylthio-thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-methoxy-thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -4-chloro-thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-vinylthieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-ethynylthieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-prop-1-ynylthieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-cyanothieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-fluorothieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-chlorothieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-bromothieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-iodothieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-trifluoromethylthieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-mercaptothieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylthio) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylamino) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (formylamino) thieno [3,2-c] pyridine-6-carboxamide; 2- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,2-c] pyridine-6-carboxamide; 2- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,2-c] pyridine-6-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(trifluoroacetyl) amino] thieno [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (benzoylamino) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diethylamino) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diisopropylamino) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-yl) thieno [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-yl) thieno [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-yl) thieno [3,2-c] pyridine-6-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-yl) thieno [3,2-c] pyridine-6-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-yl) thieno [3,2-c] pyridine-6-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (4-methylpiperazin-1-yl) thieno [3,2-c] pyridine-6 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (cyclopropylamino) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- [dimethylamino] thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-ylcarbonyl) thieno [3,2-c] pyridine-6 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-ylcarbonyl) thieno [3,2-c] pyridine-6 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(4-methylpiperazin-1-yl) carbonyl] thieno [3,2-c ] Pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-ylcarbonyl) thieno [3,2-c] pyridine-6 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (aziridin-1-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (azetidin-1-ylcarbonyl) thieno [3,2-c] pyridine-6- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-formylthieno [3,2-c] pyridine-6-carboxamide; 2-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (trifluoroacetyl) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(phenyl) sulfonyl] thieno [3,2-c] pyridine-6-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylsulfonyl) thieno [3,2-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-vinylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -7-methyl-furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -7-methoxy-furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethynylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-cyanofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-fluorofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-iodofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-mercaptofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylthio) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (formylamino) furo [2,3-c] pyridine-5-carboxamide; 3- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; 3- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(trifluoroacetyl) amino] furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (benzoylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diethylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diisopropylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-yl) furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-yl) furo [2,3-c] pyridine-5-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-yl) furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-yl) furo [2,3-c] pyridine-5-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (cyclopropylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-ylcarbonyl) furo [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(4-methylpiperazin-1-yl) carbonyl] furo [2,3-c] Pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (aziridin-1-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (azetidin-1-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-formylfuro [2,3-c] pyridine-5-carboxamide; 3-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (trifluoroacetyl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(phenyl) sulfonyl] furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylsulfonyl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -2-ethyl-furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-ethynylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-cyanofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-fluorofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-chlorofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-bromofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-iodofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-mercaptofuro [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylthio) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (formylamino) furo [2,3-c] pyridine-5-carboxamide; 2- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; 2- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(trifluoroacetyl) amino] furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (benzoylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diethylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (diisopropylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-yl) furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-yl) furo [2,3-c] pyridine-5-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-yl) furo [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-yl) furo [2,3-c] pyridine-5-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (4-methylpiperazin-1-yl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (cyclopropylamino) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (pyrrolidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperidin-1-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (piperazin-1-ylcarbonyl) furo [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(4-methylpiperazin-1-yl) carbonyl] furo [2,3-c] Pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (morpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (thiomorpholin-4-ylcarbonyl) furo [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (aziridin-1-ylcarbonyl) furo [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (azetidin-1-ylcarbonyl) furo [2,3-c] pyridine-5-carbox Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-formylfuro [2,3-c] pyridine-5-carboxamide; 2-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (trifluoroacetyl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2-[(phenyl) sulfonyl] furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -2- (methylsulfonyl) furo [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -7-methyl-thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-methylthio-thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-methoxy-thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -7-chloro-thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-vinylthieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-ethynylthieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-prop-1-ynylthieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-cyanothieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-fluorothieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-chlorothieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-bromothieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-iodothieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-trifluoromethylthieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-mercaptothieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylthio) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylamino) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (formylamino) thieno [2,3-c] pyridine-5-carboxamide; 3- (acetylamino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-c] pyridine-5-carboxamide; 3- (acetyl (methyl) amino) -N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-c] pyridine-5-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(trifluoroacetyl) amino] thieno [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (benzoylamino) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diethylamino) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (diisopropylamino) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-yl) thieno [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-yl) thieno [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-yl) thieno [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-yl) thieno [2,3-c] pyridine-5-car Boxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-yl) thieno [2,3-c] pyridine-5-carbox amides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (4-methylpiperazin-1-yl) thieno [2,3-c] pyridin-5 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (cyclopropylamino) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- [dimethylamino] thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (pyrrolidin-1-ylcarbonyl) thieno [2,3-c] pyridine-5 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperidin-1-ylcarbonyl) thieno [2,3-c] pyridine-5 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (piperazin-1-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(4-methylpiperazin-1-yl) carbonyl] thieno [2,3-c ] Pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (morpholin-4-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (thiomorpholin-4-ylcarbonyl) thieno [2,3-c] pyridine-5 Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (aziridin-1-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (azetidin-1-ylcarbonyl) thieno [2,3-c] pyridine-5- Carboxamides; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-formylthieno [2,3-c] pyridine-5-carboxamide; 3-acetyl-N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (trifluoroacetyl) thieno [2,3-c] pyridine-5-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3-[(phenyl) sulfonyl] thieno [2,3-c] pyridine-5-carboxamide ; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) -3- (methylsulfonyl) thieno [2,3-c] pyridine-5-carboxamide; Or a pharmaceutically acceptable salt, racemic mixture or pure enantiomer thereof. The compound of claim 6, wherein the azabicyclo is I, III or IV. The compound of claim 14, wherein the azabicyclo is I and R ₂ is alkyl, halogenated alkyl or substituted alkyl, or the azabicyclo is III or IV and R _2-3 is H, alkyl or substituted alkyl. The method of claim 15, N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (l- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -7-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-car Boxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3,3-dimethyl-2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -furo [2,3-b] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -furo [2,3-b] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -furo [2,3-b] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-isopropylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -7- (methylsulfanyl) furo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-c] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-c] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-c] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-c] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-c] pyridine-2-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-2-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -1-methyl-1H-pyrrolo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-bromofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-chlorofuro [2,3-c] pyridine-5-carboxamide; Or a pharmaceutically acceptable salt, pure enantiomer or racemic mixture thereof. The method of claim 16, N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2,3-dihydrofuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-methylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-ethylfuro [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-b] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [2,3-c] pyridine-5-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -thieno [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -thieno [3,2-c] pyridine-6-carboxamide; Or a pharmaceutically acceptable salt, pure enantiomer or racemic mixture thereof. The method of claim 15, N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-ethynylfuro [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-cyanofuro [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-fluorofuro [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-chlorofuro [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-bromofuro [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-iodofuro [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide; 2- (acetylamino) -N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carbox amides; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide; N-6- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide; 2-acetyl-N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxamide; Methyl 6-{[1- (6-methyl) -azabicyclo [2.2.2] oct-3-ylamino] carbonyl} furo [3,2-c] pyridine-2-carboxylate; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-vinylfuro [2,3-c] pyridine-5-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-ethynylfuro [2,3-c] pyridine-5-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-cyanofuro [2,3-c] pyridine-5-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-fluorofuro [2,3-c] pyridine-5-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-iodofuro [2,3-c] pyridine-5-carboxamide; N- [1- (6-methyl-azabicyclo [2.2.2] oct-3-yl] -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide; 3- (acetylamino) -N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carbox amides; N- [1- (6-methyl) azabicyclo [2.2.2] oct-3-yl] -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide; N-5- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide; N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] -3-formylfuro [2,3-c] pyridine-5-carboxamide; 3-acetyl-N- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxamide; Methyl 5-{[1- (6-methyl) -azabicyclo [2.2.2] oct-3-ylamino] carbonyl} furo [2,3-c] pyridine-3-carboxylate; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-ethynylfuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-cyanofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-fluorofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-chlorofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-bromofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-iodofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide; 2- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide; N-6- [1- (6-methyl) azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide; 2-acetyl-N- (2-azabicyclo [2.2.1] hept-5-yl) furo [3,2-c] pyridine-6-carboxamide; Methyl 6-[(2-azabicyclo [2.2.1] hept-5-ylamino) carbonyl] furo [3,2-c] pyridine-2-carboxylate; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-vinylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-ethynylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-cyanofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-fluorofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-iodofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide; 3- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide; N-5- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -3-formylfuro [2,3-c] pyridine-5-carboxamide; 3-acetyl-N- (2-azabicyclo [2.2.1] hept-5-yl) furo [2,3-c] pyridine-5-carboxamide; Methyl 5-[(2-azabicyclo [2.2.1] hept-5-ylamino) carbonyl] furo [2,3-c] pyridine-3carboxylate; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-ethynylfuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-prop-1-ynylfuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-cyanofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-fluorofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-chlorofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-bromofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-iodofuro [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2-trifluoromethylfuro [3,2-c] pyridine-6-carboxamide; 2- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2- (pyrrolidin-1-yl) furo [3,2-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -2- [dimethylamino] furo [3,2-c] pyridine-6-carboxamide; N-6- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2,6-dicarboxamide; 2-acetyl-N- (2-azabicyclo [2.2.1] hept-6-yl) furo [3,2-c] pyridine-6-carboxamide; Methyl 6-[(2-azabicyclo [2.2.1] hept-6-ylamino) carbonyl] furo [3,2-c] pyridine-2-carboxylate; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-vinylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-ethynylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-prop-1-ynylfuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-cyanofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-fluorofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-iodofuro [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-trifluoromethylfuro [2,3-c] pyridine-5-carboxamide; 3- (acetylamino) -N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3- (pyrrolidin-1-yl) furo [2,3-c] pyridine-5-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3- [dimethylamino] furo [2,3-c] pyridine-5-carboxamide; N-5- [1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3,5-dicarboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -3-formylfuro [2,3-c] pyridine-5-carboxamide; 3-acetyl-N- (2-azabicyclo [2.2.1] hept-6-yl) furo [2,3-c] pyridine-5-carboxamide; Methyl 5-[(2-azabicyclo [2.2.1] hept-6-ylamino) carbonyl] furo [2,3-c] pyridine-3-carboxylate; Or a pharmaceutically acceptable salt, pure enantiomer or racemic mixture thereof. The compound of claim 3, wherein W is (b). The compound of claim 19, wherein (b) is thieno [3,4-c] pyridin-6-yl, Wherein the compound is selected from F, Br, Cl, I, -CN, -NO ₂ , -CF ₃ , -OR ₅ on up to 4 different carbon atoms, as valency permits and as permitted by the definition of W; , -OR ₁₉ , -SR ₅ , -SR ₁₉ , -N (R ₅ ) ₂ , -N (R ₁₀ ) ₂ , -C (O) R ₁₉ , -CO ₂ R ₁₉ , -C (O) N ( R ₁₀ ) ₂ , -S (O) ₂ R ₁₉ , alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, aryl, R ₇ , optionally substituted with R ₉ , Additionally, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl on nitrogen as permitted by the definition of W, Optionally substituted with R ₇ or R ₉ , However, the compound which couple | bonded W to the core molecule using one carbon. The compound of claim 20, wherein the azabicyclo is II, V or VI. The compound of claim 21, wherein each k ₂ , k ₅ and k ₆ are independently 0 or 1. The compound of claim 22, wherein R ₂ is alkyl, halogenated alkyl, substituted alkyl, or R ₂ is absent when k ₂ , k ₅ or k ₆ is zero. The compound of claim 23, wherein R ₂ is absent when R ₁ is H or lower alkyl and R ₂ is lower alkyl or k ₂ , k ₅ or k ₆ is zero. The method of claim 24, N- (1-azabicyclo [2.2.1] hept-3-yl) thieno [3,4-c] pyridine-6-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) thieno [3,4-c] pyridine-6-carboxamide; N-((3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl) thieno [3,4-c] pyridine-6-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) thieno [3,4-c] pyridine-6-carboxamide; Or a pharmaceutically acceptable salt, racemic mixture or pure enantiomer thereof. The compound of claim 20, wherein the azabicyclo is I, III or IV. The compound of claim 26, wherein the azabicyclo is I and R ₂ is alkyl, halogenated alkyl or substituted alkyl, or the azabicyclo is III or IV and R _2-3 is H, alkyl or substituted alkyl. The method of claim 27, N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) thieno [3,4-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) thieno [3,4-c] pyridine-6-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) thieno [3,4-c] pyridine-6-carboxamide; Or a pharmaceutically acceptable salt, pure enantiomer or racemic mixture thereof. The compound of claim 3, wherein W is (c). The method of claim 29, wherein (c) is benzothieno [3,2-c] pyridin-3-yl, benzothieno [2,3-c] pyridin-3-yl, benzofuro [3,2-c ] Pyridin-3-yl or benzofuro [2,3-c] pyridin-3-yl, Wherein the compound is selected from F, Br, Cl, I, -CN, -NO ₂ , -CF ₃ , -OR ₅ on up to 4 different carbon atoms, as valency permits and as permitted by the definition of W; , -OR ₁₉ , -SR ₅ , -SR ₁₉ , -N (R ₅ ) ₂ , -N (R ₁₀ ) ₂ , -C (O) R ₁₉ , -CO ₂ R ₁₉ , -C (O) N ( R ₁₀ ) ₂ , -S (O) ₂ R ₁₉ , alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, aryl, R ₇ , optionally substituted with R ₉ , Additionally, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl on nitrogen as permitted by the definition of W, Optionally substituted with R ₇ or R ₉ , However, the compound which couple | bonded W to the core molecule using one carbon. The compound of claim 30, wherein the azabicyclo is II, V or VI. 32. The compound of claim 31, wherein each k ₂ , k ₅ and k ₆ is independently 0 or 1. The compound of claim 32, wherein R ₂ is alkyl, halogenated alkyl, substituted alkyl, or when R ₂ is k ₂ , k ₅ or k ₆ is zero. 34. The method of claim 33, wherein R ₁ is H or lower alkyl, or R ₂ is not present or lower alkyl, k _2, k _5, or k ₆ is 0, the compound is not R ₂ is present if the. The method of claim 34, wherein N- (1-azabicyclo [2.2.1] hept-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; N- (1- (6-methyl) -azabicyclo [2.2.1] hept-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; N-((3R, 5R) -1-Azabicyclo [3.2.1] oct-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; N- (1-azabicyclo [3.2.2] non-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] [1] benzofuro [2,3-c] pyridine-3-carboxamide; N- [exo-4 (S) -1-azabicyclo [2.2.1] hept-3-yl] [1] benzothieno [2,3-c] pyridine-3-carboxamide; Or a pharmaceutically acceptable salt, racemic mixture or pure enantiomer thereof. 31. The compound of claim 30, wherein the azabicyclo is I, III or IV. The compound of claim 36, wherein the azabicyclo is I and R ₂ is alkyl, halogenated alkyl or substituted alkyl, or the azabicyclo is III or IV and R _2-3 is H, alkyl or substituted alkyl. The method of claim 37, N- (1- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; N- (2-azabicyclo [2.2.1] hept-5-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; N- (2-azabicyclo [2.2.1] hept-6-yl) -benzothieno [3,2-c] pyridine-3-carboxamide; Or a pharmaceutically acceptable salt, pure enantiomer or racemic mixture thereof. 39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, an antipsychotic and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 39, wherein the compound and the agent are independently administered rectally, topically, orally, sublingually or parenterally at therapeutically effective intervals. The pharmaceutical composition of claim 39, wherein the compound is administered in an amount of about 0.001 to about 100 mg per kg of body weight of the mammal per day. The pharmaceutical composition of claim 39, wherein the compound is administered in an amount of about 0.1 to about 50 mg per kg of body weight of the mammal per day. 40. A pharmaceutical composition according to claim 39 comprising a compound according to any one of claims 1 to 38 and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 43, wherein the compound is administered rectally, topically, orally, sublingually or parenterally at therapeutically effective intervals. The pharmaceutical composition of claim 43, wherein the compound is administered in an amount of about 0.001 to about 100 mg per kg body weight of the mammal per day. The pharmaceutical composition of claim 43, wherein the compound is administered in an amount of about 0.1 to about 50 mg per kg of body weight of the mammal per day. 39. A compound according to any one of claims 1 to 38 for the manufacture of a medicament for the treatment of a disease or condition in which a mammal will be alleviated by administration of a therapeutically effective amount of a7 nicotinic acetylcholine receptor agonist. Use of 48. The use of claim 47, wherein the disease or condition is a cognitive and attention deficit symptom of Alzheimer's disease, neurodegeneration associated with a disease such as Alzheimer's disease, elderly dementia (mild cognitive impairment) or senile dementia. 48. The use of claim 47, wherein the disease or condition is schizophrenia or psychosis. 50. The use of claim 49, wherein the mammal will be alleviated by administering a therapeutically effective amount of a7 nicotinic acetylcholine receptor agonist and antipsychotics at therapeutically effective intervals. 48. The use of claim 47, wherein the disease or condition is depression, anxiety, general anxiety disorder or post traumatic stress disorder. 48. The use of claim 47, wherein the disease or condition is attention deficit disorder or attention deficit hyperactive disorder. 48. The method of claim 47, wherein the disease or condition is mood and emotional disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with common and brain tumors, AIDS dementia complications, dementia associated with Down syndrome. , Withdrawal symptoms associated with dementia associated with Lewy body, Huntington's disease, Parkinson's disease, delayed dyskinesia, Pick's disease, bulemia and anorexia, withdrawal associated with smoking cessation and dependent drug discontinuation, Gilles de la Tourette's Syndrome, age-related macular degeneration, glaucoma, neurodegeneration or pain associated with glaucoma. A disease in which a mammal will experience symptom relief due to the administration of an a7 nicotinic acetylcholine receptor agonist, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1-38. A method of treating a disease or condition in a mammal in need thereof. 55. The method of claim 54, wherein the disease or condition is a cognitive and attention deficit symptom of Alzheimer's disease, neurodegeneration associated with a disease such as Alzheimer's disease, elderly dementia (mild cognitive impairment), or senile dementia. 55. The method of claim 54, wherein the disease or condition is schizophrenia or psychosis. The method of claim 56, wherein the mammal will be alleviated by administering a therapeutically effective amount of α7 nicotinic acetylcholine receptor agonist and antipsychotic agent at therapeutically effective intervals. 55. The method of claim 54, wherein the disease or condition is depression or anxiety and general anxiety disorder and post-traumatic stress disorder. 55. The method of claim 54, wherein the disease or condition is attention deficit disorder or attention deficit hyperactivity disorder. 55. The method of claim 54, wherein the disease or condition is mood and emotional disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with common and brain tumors, AIDS dementia complications, dementia associated with Down syndrome , Dietary disorders involving dementia associated with Lewy body, Huntington's disease, Parkinson's disease, delayed dyskinesia, pick disease, morbidity and anorexia, withdrawal symptoms associated with quitting smoking and dependent drug discontinuation, Gilles de la Tourette syndrome, age -Related macular degeneration, glaucoma, neurodegeneration or pain associated with glaucoma.